Altered major histocompatibility complex (MHC) determinant and methods of using the determinant

ABSTRACT

An altered MHC class I determinant comprises α 1 , α 2 , α 3 , β 2  -microglobulin (β 2  m) polypeptide domains encoded by a mammalian MHC class I locus in which the α 3  domain is covalently linked to the β 2  M domain. An altered MHC class II determinant comprises α 1 , α 2 , β 1 , and β 2  polypeptide domains encoded by a mammalian MHC class II locus, in which the domains are covalently linked to form a polypeptide comprising the β 2  -α 2  -α 1  -β 1  domains in sequence. The altered MHC class I and class II determinants can be associated with an antigen to elicit an immune response. The invention can be used in the immunization or treatment of diseases such as AIDS, multiple sclerosis, lupus erythematosus, toxic shock or snake bite.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 07/801,818, filed Dec. 5,1991 pending; which is a continuation of application Ser. No.07/792,473, filed Nov. 15, 1991 abandoned, the entire disclosure ofwhich is relied upon and incorporated by reference herein.

BACKGROUND OF THE INVENTION

This invention relates to an altered major histocompatibility complex(MHC) determinant and to the altered MHC determinant in association withan antigen. This invention also relates to the use of the altered MHCdeterminant in diagnostic applications and for treating or immunizing amammal.

The major histocompatibility complex is a series of genes that code forprotein molecules responsible for cell-cell recognition and interaction.The MHC of mammalian species contains three groups of genes: class I,class II, and class III. Class I and class II genes code for cellsurface recognition molecules. Class III genes code for certaincomplement components.

The ability of cells to recognize other cells as self or as originatingfrom another genetically different individual (non-self) is an importantproperty in maintaining the integrity of tissue and organ structure.Class I and class II MHC products control recognition of self andnon-self. The major histocompatibility system thus prevents anindividual from being invaded by cells from another individual. Forexample, transplants from one individual generally cannot survive inanother individual because of histocompatibility differences.

Histocompatibility similarities are required for cellular cooperation ininduction of the immune response, and they provide a mechanism to ensurethat T cells and B cells of a given individual can recognize each otherfor cooperation, yet recognize foreign structures at the same time. Forinstance, T lymphocytes, when presented with an antigen in the propermanner, react in one of two ways: through the generation of T cytotoxiclymphocytes (T_(c)) or through amplification by T helper cells (T_(h))or suppression by T suppressor cells (T_(s)) of the effects of other Tor B cells. In general, T lymphocytes only recognize the antigen andrespond to it when it is presented on the surface of antigen-presentingcell. This antigen-presenting cell may vary according to the type of Tlymphocyte involved. Thus, in the generation of cytotoxic responses,lymphocytes and possibly macrophages present the antigen to the T_(c)cells, while in the other types of T response the presenting cell may bea macrophage and perhaps dendritic cells.

T cells need to recognize two structures, a foreign antigen and an MHCgene product, for their subsequent activation. The process of generatingT_(c) cells and a cytotoxic response requires that the antigen bepresented to the T cells in association with an MHC class I geneproduct. On the other hand, for B cells to be activated, binding to theantigen is necessary, plus a second signal usually given by a T_(h)lymphocyte. However, the T_(h) lymphocytes require the presentation ofthe antigen in a processed form by an antigen-presenting cell in thecontext of an MHC class II determinant.

In the case of B cell activation, it has been established that whateverthe antigen-presenting cell is, it must process the antigen beforepresenting it to the T_(h) lymphocytes. This involves taking up theantigen, sequestering it in intracellular compartments, andre-expressing the antigen or a portion thereof on the surface of theantigen-presenting cell in association with a class II MHC determinant.The T_(h) cell must be able to recognize the processed antigen and classII markers on both the antigen-presenting cell and the B cell. When eachof these requirements is fulfilled, the B cell will be stimulated toproliferate, which greatly increases the number of cells capable ofsynthesizing specific antibody. These then differentiate into plasmacells, which secrete large amounts of antibody. A similar responseemploying class II receptors on T_(s) suppressor cells and class II MHCmarkers on macrophages and B cells may be operative in induction of Tsuppressor activity, which turns off antibody production.

Much remains to be understood of the interactions between antigens andMHC class I and class II molecules, and of the way in which T cellreceptors recognize MHC-antigen complexes. For instance, a largeproportion of MHC molecules is likely to be occupied by a variety ofpreexisting (probably endogenous) peptides. This obscures theinterpretation of peptide-binding assays and hampers crystallographicstudies of peptide-MHC complexes. It would be extremely useful to beable to isolate peptide-free MHC molecules, which could be loaded by asingle type of peptide.

In addition, there exists a need in the art for knowledge of the peptidemotifs of individual MHC alleles to aid in making T-cell epitopepredictions, to aid in synthetic or recombinant vaccine development, andfor intervention in autoimmune diseases or graft rejection.

SUMMARY OF THE INVENTION

This invention aids in fulfilling these needs in the art. Moreparticularly, this invention provides a MHC class I determinantcomprising α₁, α₂, α₃ and β₂ -microglobulin polypeptide domains encodedby a mammalian MHC class I locus. The α₃ domain has a carboxyl terminus,and the β₂ -microglobulin domain has an amino terminus that iscovalently linked to the carboxyl terminus of the α₃ domain.

This invention also provides a MHC class II determinant comprising α₁,α₂, β₁, and β₂ polypeptide domains encoded by a mammalian MHC class IIlocus. The domains are covalently linked to form a polypeptidecomprising the β₂ -α₂ -α₁ -β₁ domains in sequence.

In addition, this invention provides a recombinant DNA moleculecomprising the MHC class I determinant or the MHC class II determinantof the invention inserted in a vector.

Further, this invention provides a host transformed with the vector ofthe invention.

Also, this invention provides a composition comprising an antigen boundto the MHC class I determinant or the MHC class II determinant of theinvention.

Moreover, this invention provides a method of eliciting an immune systemresponse in a mammal. The method comprises administering to the mammalan effective amount of the MHC class I or class II determinant of theinvention, with or without association with an antigen.

Although native MHC molecules can be highly complicated structures notlending themselves to convenient manipulation, the present inventiondemonstrates the feasibility of creating MHC-antigen complexes betweenany of a variety of molecules capable of fulfilling the task of targetrecognition. These molecules are easier to handle and refold during andafter denaturing treatments. These constructs are useful in the analysisof functional interactions between the various domains comprising theMHC molecules.

Moreover, this invention makes it possible to intervene in thefunctioning of the immune system. The immune system cells are capable ofrecognizing the altered MHC determinants and compositions of theinvention and to respond to the presence of a potential pathogen with aneffector appropriate to its lineage, e.g., cytotoxic T lymphocytes wouldrespond by cytotoxic activity against the target, and B lymphocytes areactivated to synthesize antibody. Macrophages and granulocytes carry outtheir effector functions, including cytokine release, phagocytosis, andreactive oxygen generation after intervention by the altered MHCdeterminants and compositions of the invention. Similarly, with anantigen or peptide portion typical as a marker for tumor cells, theimmune system response to the tumor is beneficially elevated. Inaddition, with an antigen capable of causing recognition of immune cellshaving an inappropriate reactivity with self-determinants, thisinvention makes it possible to selectively target cells for destruction.

BRIEF DESCRIPTION OF THE DRAWINGS

This invention will be described in greater detail by referring to thedrawings in which:

FIG. 1 depicts the orientation of an MHC class I molecule and β₂-microglobulin in a cell membrane.

FIG. 2 depicts the orientation of an MHC class II molecule in a cellmembrane.

FIG. 3A diagrammatically depicts an altered class I MHC determinant ofthe invention.

FIG. 3B is a block diagram showing the altered class I MHC determinantof the invention and a spacer covalently linking the MHC gene produce toβ₂ -microglobulin.

FIG. 4A depicts an altered class II MHC determinant of the invention.

FIG. 4B is a block diagram showing the domains of the altered class IIMHC determinant of the invention linked by spacers.

FIGS. 5A and 5B depicts DNA constructs of the parental plasmid,pSC-K^(d) -2, in 5A (SEQ ID No:1 and SEQ ID No:2). Various spacers aredepicted in (5B). Spacer SC-10 corresponds to SEQ ID NO:3 and SEQ IDNO:4; spacer SC-13 corresponds to SEQ ID NO:5 and SEQ ID NO:6; spacerSC-15 corresponds to SEQ ID NO:7 and SEQ ID NO:8; spacer SC-17corresponds to SEQ ID NO:9 and SEQ ID NO:10; spacer SC-19 corresponds toSEQ ID NO:11 and SEQ ID NO:12; and spacer SC-21 corresponds to SEQ IDNO:13 and SEQ ID NO:14.

FIG. 6A-D shows the immunodetection of intracellular SC-K^(d) molecules:

(6A) Immunoprecipitation of SC-K^(d) -2, -10, -13, -17, -19, -21 by mAb34-1-2. NT refers to "non-transfected" and pKC refers to transfection bythe vector. Transfections were made in the absence (-) or in thepresence (+) of a peptide (NPR⁻) added at a concentration of 10⁻⁴ M inthe culture medium.

(6B) Immunoprecipitation of SC-K^(d) -2, -15 by monoclonal antibody(mAb) 34-1-2 (left), F23-1 (middle) and 20-8-4 (right). Symbols asabove.

(6C) Immunoprecipitation of SC-K^(d) -15 treated (+) and non-treated (0)with Endo H.

(6D) Overexposed autoradiogram [3 weeks instead of 2 days in (A) and(B)] showing the presumptive monkey β₂ -microglobulin band, which isco-precipitated by 34-1-2 in larger relative amounts with SC-K^(d) -2than with SC-K^(d) -15 (on top, with a 2-day exposure).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

The invention concerns construction of functional molecules capable ofactivating the immune system and capable of presenting antigens to theimmune system to elicit an antigenic response. More particularly, itconcerns the regulation of the immune system response by presentingantigen via an altered MHC determinant so as to cause T-cells to respondto the determinant or the presented antigen. The invention also concernsa method of immunization and therapy for diseases as varied as AIDS,lupus erythematatosus, multiple sclerosis, toxic shock, and snake bite.

1. Major Histocompatibility Complex ("MHC")

All nucleated cells express class I MHC gene products on their surface.Class II gene products are expressed on some cells, such as B cells andmacrophages, but not on other cells. This invention provides an alteredmajor histocompatibility complex determinant of a mammal.

The term "major histocompatibility complex" is abbreviated herein as"MHC". The term is used in describing this invention in a generic senseto refer to the set of genes that code for histocompatibility markers inmammals. Exemplary of the mammalian species from which the altered MHCdeterminants of the invention can be based are the species identified inTable 1.

                  TABLE 1                                                         ______________________________________                                        MHC nomenclature of mammalian species                                                Species     MHC designation                                            ______________________________________                                        Chimpanzee     ChLA                                                             Dog DLA                                                                       Guinea pig GPLA                                                               Human HLA                                                                     Mouse H-2                                                                     Pig SLA                                                                       Rabbit RLA                                                                    Rat RT1                                                                       Rhesus monkey RhLA                                                          ______________________________________                                    

Where reference is made herein to the MHC of a particular mammalianspecies, the MHC designation in Table 1 will be employed.

2. Class I And Class II Major Histocompatibility Complex Gene Products

Class I MHC gene products are glycoproteins that are noncovalently boundto a peptide termed β₂ -microglobulin, which is abbreviated "β₂ m" or"β₂ M". The class I component is referred to as the heavy chain and theβ₂ -microglobulin as the light chain. The orientation of the MHC class Imolecule and β₂ -microglobulin in a cell membrane is illustrated in FIG.1.

Referring to the Figure, the heavy chain structure is organized withthree exposed domains, α₁, α₂, and α₃, which extend from the cellsurface and are attached to a hydrophobic transmembrane domain 1 and ashort cytoplasmic anchor segment 2 within the cell. Two of the outerdomains (α₂ and α₃) have intrachain disulfide bonds (forming loops withconsiderable homology with Ig).

The light chain (β₂ -microglobulin) shown in the Figure is about thesame size as one of the α domains of the heavy chain. Each domain isimmunoglobulin-like, consisting of a folded β pleated sheet structureheld together by a disulfide bond at the ends, giving a plane-likesurface. The β₂ chain folds with the α₃ domain of the heavy chain, andthe α₁ and α₂ domains also pair.

The β₂ -microglobulin gene is located on a chromosome different fromthat containing the MHC class I gene product. Its structure is highlyconserved, whereas that of the heavy chains varies extensively from oneindividual to another because of differences in amino acid sequences ofthe external domains. The polymorphism of the heavy chain is contributedprimarily by the α₁ domain and to a lesser degree by the α₂ domain.

The products of the class II genes are less well characterized. In themouse, the class II gene product (Ia) consists of two polypeptide chains(α and β, FIG. 2). The α and β chains are divided into two externaldomains (α₁ and α₂ or β₁ and β₂), transmembrane domains 3 and 4 in FIG.2, and cytoplasmic domains 5 and 6. Cystein residues that participate indisulfide bridge formation are indicated by S in FIG. 2.

The class I and class II MHC gene products may be glycosylated.

3. Altered Class I And Class II MHC Determinants Of The Invention

This invention involves altered determinants corresponding to productsof class I and class II MHC loci. This invention also involves analtered MHC class I or class II determinant with an antigen to form acomposition that can be recognized by the immune system of a mammal toinitiate an immune or cytolytic response.

An altered class I MHC determinant substantially free of associatedantigen is diagrammatically depicted in FIG. 3A in which the α₃ domainof the heavy chain is linked to the β₂ -microglobulin domain by means ofa spacer (shown as a broken line in the Figure). The resulting product,which is depicted in block diagram form in FIG. 3B, is the altered classI MHC determinant of this invention and comprises the α₁, α₂, α₃, and β₂-microglobulin domains covalently linked in sequence. As shown in FIG.3A, the α₃ domain of the heavy chain is free of the region proximate thetransmembrane domain region 1 in FIG. 1 to the carboxyl terminus of thecytoplasmic segment 2.

The altered class I MHC determinant can be prepared by appropriateselection of the MHC locus encoding the α₁, α₂, α₃ domains, and a geneencoding the β₂ -microglobulin domain so that each of these domains willretain their functions in activating cytotoxic T cells and in antigenpresentation to mammalian T cell receptors. Expression of thepolypeptide coded by the MHC locus can be achieved by recombinant DNAtechniques described in detail hereinafter.

An altered class II MHC determinant of the invention is shown indiagrammatic form in FIG. 4A. Referring to the Figure, the aminoterminus of the α₁ domain is joined to the carboxyl terminus of the β₁domain, such as by means of a spacer (broken line). Similarly, thecarboxyl terminus of the α₂ domain is joined to the amino terminus ofthe β₂ domain, such as by means of another spacer (broken line). Theresulting product is the altered class II MHC determinant of thisinvention, which can be represented by the block diagram shown in FIG.4B. The altered determinant comprises the β₂, α₂, α₁, and β₁ domainscovalently linked in sequence. As shown in FIG. 4A, the altereddeterminant is free of the regions proximate the transmembrane domains 3and 4 in FIG. 2 extending to the carboxyl termini of the cytoplasmicsegments 5 and 6, which are normally affixed to the α₁ -α₂ chain and theβ₁ -β₂ chain, respectively. Once again, the portions of the MHC loci areselected to preserve the function of the domains in stimulating acytotoxic response or in presenting antigen to mammalian T cellreceptors.

4. Polypeptides Encoded By MHC

The altered major histocompatibility complex determinant of theinvention is a polypeptide encoded by the genetic loci of class I orclass II mammalian MHC and β₂ m genes, where the polypeptide contains abinding site for an antigen that may be associated with the polypeptide,and when associated, the polypeptide and the antigen together arerecognizable by a mammalian T cell receptor. In the case of human classI determinants, the determinant can be a polypeptide encoded by any ofgenetic loci identified in Table 2, as well as genetic loci not listedand/or not yet discovered.

                  TABLE 2                                                         ______________________________________                                        HLA class I loci                                                                    HLA-A        HLA-B        HLA-C                                           Allele Allele Allele                                                        ______________________________________                                        A1             B7           Cw1.sup.b                                           A2 B7 Cw2                                                                     A3 B13 Cw3                                                                    A11 B18 Cw4                                                                   A23 B27 Cw5                                                                   A24 B35 Cw6                                                                   A25 B37 Cw7                                                                   A26 B38 Cw8                                                                   A28 B39                                                                       A29 Bw31                                                                      A30 Bw42                                                                      A31 B44                                                                       A32 B45                                                                       AW33 B49                                                                       Bw50                                                                          B51                                                                           Bw52                                                                          Bw53                                                                          Bw54                                                                          Bw55                                                                          Bw57                                                                          Bw58                                                                          Bw60                                                                          Bw61                                                                          Bw62                                                                          Bw63                                                                          Bw64                                                                          Bw65                                                                       ______________________________________                                         "w" designates workshop specificity not yet given accepted status             according to WHO nomenclature rules.                                     

In the case of human class II MHC determinants, the polypeptide employedin this invention can be encoded by any of the genetic loci in Table 3,as well as loci not listed here or not yet discovered.

                  TABLE 3                                                         ______________________________________                                        HLA class II loci                                                                  Allele     Allele     Allele   Allele                                    ______________________________________                                        Dw1a        DR1        DQw1       DPw1                                          Dw2 DR2 DQw2 DPw2                                                             Dw3 DR3 DQw3 DPw3                                                             Dw4 DR4  DPw4                                                                 Dw5 DR7  DPw5                                                                 Dw8 DRw8  DPw6                                                                Dw9 DRw9                                                                      Dw10 DRw10                                                                    Dw11 DRw11                                                                    Dw12 DRw12                                                                    Dw13 DRw13                                                                    Dw14 DRw14                                                                    Dw17                                                                          Dw18                                                                          Dw19                                                                        ______________________________________                                         "w" designates workshop specificity not yet given accepted status             according to WHO nomenclature rules.                                     

The polypeptide employed in this invention can be based on an MHCdeterminant other than human species. Thus, for example, the polypeptidecan be encoded by any of the genetic loci described in Table 4, whichidentifies MHC loci of the mouse.

                  TABLE 4                                                         ______________________________________                                        H-2 MHC loci                                                                  ______________________________________                                        Class     I      II     II   II   II   I    I                                   Products K Aβ Aα Eβ Eα D L                            ______________________________________                                    

It will be understood that the present invention is intended toencompass the altered MHC class I and class II determinants of theinvention in the form in which they are prepared in situ or in purifiedform. In addition, the invention encompasses the altered determinantswhether or not fully glycosylated and whether obtained using thetechniques described herein or other methods. In a preferred embodimentof this invention, the altered MHC class I and class II determinants aretotally free or substantially free of one or more of the followingcomponents: mammalian tissue and mammalian tissue components, nucleicacids, extraneous proteins and lipids, and adventitious microorganisms,such as bacteria and viruses. It will also be understood that theinvention encompasses equivalent determinants having substantially thesame biological and immunogenic properties. Thus, this invention isintended to cover variants of MHC determinants.

Depending upon the use to be made of the altered MHC class I and classII determinants, it may be desirable to label them. Examples of suitablelabels are radioactive labels, enzymatic labels, fluorescent labels,chemiluminescent labels, and chromophores. The methods for labeling thealtered determinants of the invention do not differ in essence fromthose widely used for labeling immunoglobulin. The need to label may beavoided using labeled antibody to the altered determinants oranti-immunoglobulin to the antibodies to the altered determinants as anindirect marker.

5. Joining the Polypeptide Domains of the Altered MHC Determinant

The domains of the altered MHC determinants correspond to domainsencoded by naturally occurring MHC loci and variants thereof that encodeMHC products capable of effecting a cytotoxic response by appropriate Tcells or inducing an immune response by the lymphocyte. The altered MHCclass I and class II determinants of the invention differ from naturallyoccurring mammalian MHC gene products in that domains of the geneproducts are covalently linked, such as by means of a spacer. Forexample, in class I MHC gene products in nature, the class I heavy chainis always non-covalently associated with β₂ -microglobulin. In contrast,the altered class I determinant of the invention comprises the class Iheavy chain covalently linked to the β₂ m domain. Similarly, the alteredMHC class II determinant of the invention is comprised of a polypeptidechain in which the β₂ -α₂ -α₁ -β₁ domains are covalently linked. Thesedomains are never linked in this way in nature. The altered MHC class Iand class II determinants are the same as the corresponding MHC geneproducts in nature in other respects.

The altered MHC determinants of the invention can be obtained from DNAconstructs encoding the MHC domains such that there is readthroughtranslation. For example, in the case of class I MHC determinants, theDNA construct contains a DNA sequence encoding the α₁, α₂, and α₃domains linked to a DNA sequence encoding the β₂ m domain so that thereis readthrough translation from the 5' end of the DNA encoding the α₁domain to the 3' end of the DNA sequence encoding the β₂ m domain.Similarly, the altered class II MHC determinants of the invention can beobtained from DNA constructs in which there can be readthroughtranslation of a DNA sequence encoding the β₂ -α₂ -α₁ -β₁ domains.

It was surprisingly discovered that despite the covalent linkage of theMHC domains, the resulting altered MHC class I and class II determinantsof the invention mimic the unaltered MHC class I and class II geneproducts that occur in nature.

In one embodiment of this invention, the MHC domains are covalentlylinked by a spacer, which is a nucleotide sequence encoding apolypeptide that functions as a hinge in the altered determinant. Thespacer allows efficient folding or refolding of the domains with respectto each other such that the altered determinant has the ability to bindantigen or to stimulate the immune system.

The nucleotide sequence of the spacer and the corresponding amino acidsequence have not been found to be critical to the successful practiceof this invention. Similarly, the size of the spacer has not been foundto be critical. The spacer will generally be of a size to encode apolypeptide of about 2 to about 30 amino acids, and preferably about 5to about 15 amino acids. Particularly preferred spacers encodepolypeptides having about 10 to about 15 amino acids.

A typical spacer for use in a DNA construct encoding an altered H-2determinant of the invention comprises all or part of the followingnucleotide sequence:

    (SEQ ID NO:15)                                                                          5' GATCGGATCCGGAGGCGGTGGATCCGGTGGCGGCGGTTC 3'                          - (SEQ ID NO:16) 3'     CCTAGGCCTCCGCCACCTAGGCCACCGCCGCCAAGCTAG 5'     

As another example, all or part of the following nucleotide sequence canbe employed to form a spacer of up to 15 amino acids for an alteredHLA-A2 determinant of the invention:

    (SEQ ID NO:17)                                                                            5'GGT GGC GGT GGA TCA GGC GGT GGT                                    -    CCA CCG CCA CCT AGT CCG CCA CCA                                          - (SEQ ID NO:18)   Gly Gly Gly Gly Ser Gly Gly Gly                            -    GGG TCG GGT GGC GGC GGA TCC 3'                                           -    CCC AGC CCA CCG CCG CCT AGG                                              -    Gly Ser Gly Gly Gly Gly Ser                                       

This sequence can be inserted after the nucleotides encoding amino acid274 of HLA-A2 and before the nucleotides encoding amino acid 1 of humanβ₂ -microglobulin resulting in the construction depicted in blockdiagram form in FIG. 3B.

It will be understood that this invention contemplates the use of thealtered MHC determinants in non-cross-linked or cross-linked form. Itwill also be understood that the altered MHC determinant can be loadedwith antigen without unfolding the antigen binding domain. Nevertheless,the invention contemplates unfolding the domain, for example in 7M urea,and dialysis.

6. Antigens Presented In Association With The Altered MHC Determinant

T cells can recognize synthetic peptides loaded on MHC class I and classII molecules. This phenomenon is called MHC restriction. The altered MHCclass I determinants and class II determinants of this invention arecapable of MHC restriction by association with antigens that arerecognizable by T cell receptors of mammalian cells. Crystallography ofhuman MHC class I molecules, HLA-A2 and Aw68, revealed a groove made upby the α₁ and α₂ domains of heavy chains. This groove is believed to bethe binding site for antigens. The altered MHC class I determinants ofthe invention include a binding site of this type for antigens.

More particularly, this invention makes it possible to present antigensto the mammalian immune system and to elicit an immune response in vivoor in vitro. The antigen presented in association with the altered MHCdeterminant of this invention is-generally a peptide. The antigensrecognized by MHC class I and class II restricted T cells can bemimicked by artificial peptides. The peptide can also be a naturallyoccurring peptide. Thus, the peptide can be isolated from a source inwhich it occurs in nature or the peptide can be chemically synthesized.

When the antigen associated with the altered MHC determinant of thisinvention is a peptide, the peptide will typically contain about 5 toabout 20 amino acid residues, preferably 8, 9 or 10 amino acid residues,when altered class I MHC molecules are used. Longer peptides can beemployed. with the altered MHC class II determinants of the inventionOctamers, nonomers, and decamers are particularly preferred peptides.

The naturally occurring peptides that normally bind to MHC gene productscan be modified at one or more positions by other amino acids. In thisevent, it will be understood that the modified peptide will notnecessarily have the same binding characteristics as the native orunmodified peptide; that is, a distinct allele-specific peptide motifcapable of being presented by each MHC determinant may be observed. Inany event, the peptide motifs typically contain two anchor positionsoccupied by a fixed amino acid residue or by one of a few residues withclosely related side chains. These anchor positions are not in the sameplace in the different motifs. In general, the structure of the peptideshould match the peptide-binding cleft of the altered MHC determinant.Thus, the allele-specific pockets in the altered MHC determinants ofthis-invention and the side chains of the allele-specific anchorresidues should preferably have complementary structures. Following areguidelines for selecting peptide/MHC combinations.

The physical association of antigenic peptides and altered MHC class Iand class II determinants of the invention can be monitored using adirect peptide binding assay (PBA) in solid phase or an inhibitionpeptide binding assay (IPBA) in which the competing peptide is presentin a soluble phase. Other tests measuring changes in fluorescence of anappropriately labeled peptide in soluble form when binding to a solubleMHC, or altered MHC molecule, are also available. The ability ofdifferent peptides to inhibit the lytic activity of human antiviralcytolytic T cells toward cells incubated with the corresponding targetpeptide can also be examined as a measure of the effectiveness ofantigen binding and presentation.

In general: (a) Binding of a given human T cell-recognized peptide toseveral HLA class I and class II molecules occurs occasionally.Nevertheless, preferential binding of peptides to their respectiverestriction molecules is also observed. (b) Binding of HLA molecules topeptides recognized by murine T cells occurs less frequently, but suchmechanisms are contemplated by this invention. (c) There exist HIV-1peptides containing agretopic residues which allow their binding to HLAmolecules and are particularly interesting in the scope of theinvention. (d) The kinetics of HLA/peptide association depend on thepeptide tested and are faster than or similar to those for Ia molecules.(e) Peptide/HLA molecule binding is frequently dependent on length,number of positive charges, and presence of hydrophobic residues in thepeptide. (f) A correlation may be observed between a peptide inhibitoryeffect in the IPBA and its blocking effect in the cytolytic test.

Examples of typical peptides that can be combined with the altered MHCdeterminants of this invention are given in Table 6.

                                      TABLE 6                                     __________________________________________________________________________    Peptides for Binding to Altered MHC Determinants                                       SEQ.                   Restricting                                     Peptide ID NO: Sequence Element                                             __________________________________________________________________________    Influenza A virus                                                               Matrix                                                                        M.57-68 19 KGILGFVFTLTV HLA-A2                                                M.Y.sup.+ 57-68 20 YKGILGFVFTLTV HLA-A2                                       NUCLEOPROTEIN                                                                 N.147-158R.sup.- 21 TYQRTRALVTG H-2 K.sup.D                                   N.335-349Y.sup.+ 22 SAAFEDLRVLSFIRGY HLA-B37                                  Haemagglutinin                                                                H.130-142 23 HNTNGVTAACSHE Ia.sup.d                                           H.305-329 24 CPKYVKQNTLKLATGMRNVPEKQTR HLA-DR                                 Lysozyme: Lys.46-61 25 NTDGSTDYGILQINSR Ia.sup.k                               repressor: R.12-26 26 LEDARRLKAIYEKKK Ia.sup.d                               HLA-A2: A2.170-185 27 RYLENGKETLQRTDAP H-2 K.sup.d                            HIV 1                                                                       GAG.                                                                              51-65                                                                              28  LETSEGQRQILGQLQ                                                     205-219 29 ETINEEAAEWDRVHP --                                                 219-233 30 HAGPIAPGQMREPRG --                                                 265-279 31 KRWIILGLNKIVRMY HLA-B27                                            378-391 32 MQRGNFRNQRKIVK --                                                  418-433 33 KEGHQMKDCTERQANF HLA-A2                                           Env. 105-117 34 HEDIISLWDQSLK Ia*                                              312-327 35 IRIQRGPGRAFVTIGK H-2 D.sup.d                                       428-445 36 FINMWQEVGKAMYAPPIS Ia*                                             474-489 37 RPGGGDMRDNWRSELY --                                                510-521 38 VVQREKRAVGIG --                                                    584-604 39 RILAVERYLKDQQLLGIWGCS HLA, C1 II*                                  827-843 40 YVAEGTDRVIEVVQGACR --                                              846-860 41 RHIPRRIRQGLERIL --                                                Nef.  66-80 42 VGFPVTPQVPLRPMT --                                               79-94 43 MTYKAAVDLSHFLKEK --                                                 113-128 44 WIYHTQGYFPDWQNYT HLA-B17.37                                        132-147 45 GVRYPLTFGWCYKLVP HLA-B18                                           137-145 46 LTFGWCYKL --                                                       160-174 47 ENTSLLHPVSLHGMD --                                                Vif.  1-15 48 MENRWQVMIVWQVDR --                                                25-40 49 VKHHMYVSGKARGWFY --                                                  46-60 50 SPHPRISSEVHIPLG --                                                   60-72 51 GDARLVITTYWGL --                                                     71-85 52 GLHTGERDWHLGQGV --                                                 Ref.  1-16 53 MAGRSGDSDEDLLKAV --                                               18-30 54 LIKFLYQSNPPPN --                                                     37-50 55 ARRNRRRRWRERQR --                                                  Vpr.  1-14 56 MEQAPEDQGPQREP --                                                 55-68 57 AGVAEIIRILQQLL --                                                    68-80 58 LFIHFRIGORHSR --                                                 __________________________________________________________________________     *Not precisely identified restricting element.                           

Examples of other peptide epitopes that can be associated with thealtered MHC determinants of this invention are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                        Additional Peptides for Binding                                                 to Altered MHC Determinants                                                                   SEQ                                                           Sequence ID NO: Protein source                                              ______________________________________                                        T Y O R T R A L V                                                                           128     Influenza PR8 NP 147-154                                  S Y F P E I T H I   129 Self-peptide of P815                                  I Y A T V A G S L 130 Influenza JAP HA 523-549                                V Y Q I L A I Y A 131 Influenza JAP HA 523-549                                   N V G T Y V 132 Influenza PR8 HA 518-528                                      E N G K E T 133 HLA-A24 170-18233                                          R Y L K N G K E T 134 HLA-Cw3 170-186                                         K Y Q A V T T T L 135 P815 tumour antigen                                     S Y I P S A E K I 136 Plasmodium berghei CSP 249-260                          S Y V P S A E Q I 137 Plasmodium yoelii CSP 276-288                           Known epitopes, aligned                                                       A S N E N M E T M   138 Influenza NP366-374                                   S G P S N T P P E I§ 139 Adenovirus E1A                                  S G V E N P G G Y C L§ 140 Lymphocyte choriomeningitis                     virus GP 272-293                                                            S A I N N Y . . . 141 Simian virus 40 T 192-211                               Known epitopes, aligned                                                       R G Y V Y O G L   142 Vesicular stomatitis virus                                NP 52-59                                                                    S I I N F E K L 143 Ovalbumin 258-276§                                   A P G N Y P A L 144 Sendai Virus NP 321-332                                   Known epitopes, aligned                                                       I L K E P V H G V 145 HIV reverse transcriptase                                 461-485                                                                     F L Q S R P E P T 146 HIV Gag protein 446-460§                           A M Q M L K E . . . 147 HIV Gag protein 193-203§                         Q M K D C T E R Q 148 HIV Gag protein 418-443§                         ______________________________________                                    

The antigens described in Tables 6 and 7 are merely representative ofantigens that can be presented to cell receptors in association with thealtered MHC determinants of this invention. Other antigens that formcomplexes with the determinants can also be employed. Using both thedirect peptide binding assay (PBA) and the inhibition of peptide bindingassay (IPBA), the physical interactions between HLA molecules andpeptides can be analyzed. More particularly, the assays can be carriedout as follows.

Direct Peptide Binding Assay. Wells of microtiter plates are pretreatedwith 100 μl 2.5% glutaraldehyde in distilled water for 2 h at 20° C.,washed with distilled water, and coated for 16 h at 4° C. with 100 μl ofpeptide diluted at 5 μg/ml either in carbonate-bicarbonate buffer, pH9.6, or in PBS, pH 7.4 or pH 5.0. Remaining free sites are blocked byincubation for 2 h at 20° C. with BSA diluted 1% in PBS containing 0.05%Tween 20 (Tw) and 0.02% sodium azoture. After washing, purified ¹²⁵I-HLA molecules (100 μl containing 1.5×10⁵ cpm, 10⁻⁹ M) diluted in PBScontaining 1% BSA, 0.05% Tw, 0.02% sodium azoture, 1 mM PMSF, and 10μg/ml trypsin inhibitor are added and incubated for 20 h at 20° C. Afterextensive washing, the radioactivity of each well is counted.

Inhibition Peptide Binding Assay. Concentrations of 0.1-100 μM ofcompetitor peptides are incubated in tubes for 0-3 h at 20° C. with ¹²⁵I-HLA (10⁻⁹ M) diluted in PBS--BSA--Tw containing the proteaseinhibitors as mentioned above. Then the mixture is added to microtiterplate wells coated with a peptide that shows significant binding to HLAmolecules in the direct test and incubated 20 h at 20° C. Afterextensive washing, the radioactivity in each well is counted and thepercent of inhibition is calculated.

Competition between Peptides in a Lytic Assay. Human antipeptide CTL isgenerated (37). Briefly, 6-8×10⁷ PBMC are stimulated with 100 μg of asynthetic peptide in 10 ml culture medium (RPMI 1640 supplemented with100 μg/ml penicillin, 100 μg/ml streptomycin, 2 mM L-glutamin, 2 mMnonessential amino acids, 1 mM sodium pyruvate, 10 mM Hepes, and 10%pooled heat-inactivated human AB serum). After a 7-d incubation, asecondary in vitro stimulation is performed by mixing 5-7×10⁶ effectorcells with 2-3×10⁷ irradiated (4,000 rad) autologous PBMC in 10 mlculture medium containing 50-100 μg of peptide.

In most cases, T cell epitopes are recognized in association with only afew, if not a single, MHC restriction elements. In contrast, somepeptides can be recognized in association with several H-2 or HLAmolecules. Furthermore, a single peptide can be recognized by both MHCclass I and class II restricted T cells. Since class I and class IImolecules have a similar predicted tertiary structure, including asingle antigen binding site, interactions between peptides and these twotypes of molecules are also contemplated by this invention. Moreover, itwill be understood that this invention contemplates the binding ofantigens normally associated with the MHC of one species, such as H-2,to the altered MHC determinant of another species, such as HLA.

The formation of compositions comprising antigens bound to the alteredMHC determinants of the invention can be based on peptides known to beantigenically involved in diseases such as AIDS (gag, nef, vif, ret,vpr, or env proteins or peptides), multiple sclerosis (myelin basicprotein), toxic shock (bacteria), or snake venom (antigenic region forparticular snake venom, alkaloid based and proteinaceous based; currentsnake bite therapy is based on administration of antibodies to theparticular venom). These compositions can be formulated so as to allowthe target recognition potential of an immune system cell to bespecifically redirected to the antigen in presentation with the alteredMHC determinant. It will be understood that libraries comprised ofdifferent altered MHC determinants of the invention and associatedantigens can be prepared. It is thus possible to formulate compositionscomprising two or more of the members of the library in any combinationor amount, such as for simultaneously or sequentially targetingdifferent receptors.

The extent of loading of the altered MHC determinant with peptidevaries. The altered MHC determinant is typically employed in an amountof about 10 to about 1000 μg/ml and the peptide is employed in an amountof about 10 to about 1000 μg/ml.

While this invention has been described with reference to the use ofpeptides for binding altered MHC determinants, it will be understoodthat other antigenic materials can be employed. For example, peptidescombined with haptens in general can be employed. Peptides can becombined with metals, such as nickel. Peptides can also be combined withcarbohydrates. Certain chemicals, such as p-benzoyl arsonate, also binddirectly in the groove of MHC materials. Suitable antigens are reviewedby P. Kourilsky and J. M. Claverie in "Advances in Immunology" (1989).

Similarly, the altered MHC determinants of the invention can be loadedwith conventional immunotoxins and directed to a T cell associated withautoimmune disease for the purpose of disabling the T cell. Diptheriatoxin, or subunits thereof, and Pseudomonas A toxin are examples ofsuitable immunotoxins.

7. Binding To Lymphocyte Cell Receptors

The altered MHC class I and class II determinants of the invention andcompositions comprising antigens bound to the altered determinants arerecognizable by receptors on T lymphocytes.

More particularly, the antigen and MHC recognition structure of T cellsis referred to herein as the T cell receptor. The T cell receptorinvolved in antigen and MHC recognition is characterized in Table 8.Variable regions of the α- and β-chains form the antigen binding siteand also determine MHC specificity. In the presence of antigen and MHC,the T cell is activated. This results in phosphorylation of at least twosubunits of the receptor complex, the δ- and ε-chains.

                  TABLE 8                                                         ______________________________________                                        Surface Structures Involved in Antigen                                          Recognition by Human T Lymphocytes                                                     Molecular Weight                                                   Chains     Nonreduced Reduced    Function                                     ______________________________________                                        A. T Cell receptor                                                                       90,000     41,000-43,000                                                                            Dual recognition                               complex α and β  (two chains) of antigen and                          MHC                                                                        "T.sub.3 complex" - δ 23,000 23,000 Phosphorylated                         during cell                                                                   activation                                                                 γ 20,000-23,000 20,000-23,000 Unknown                                   ε 20,000 20,000 Phosphorylated                                           during cell                                                                   activation                                                                 ζ 32,000 16 Unknown                                                        (two chains)                                                                B. T.sub.4 (CD4) 62,000 62,000 MHC class II                                      recognition                                                                C. T.sub.8 (CD8) 76,000 31,000-33,000 MHC class I                                recognition                                                              ______________________________________                                    

Two other chains on the T cell surface, T₄ (CD4) and T₈ (CD8), areassociated with the recognition of the altered class I or class II MHCdeterminants of the invention, without interacting with antigen. Thesemolecules may normally bind non polymorphic (constant) determinants onclass I or class II gene products of the antigen presenting cell. Thesemolecules may also be associated with the T cell receptor.

A summary of the relationship between MHC class I and class II moleculesand the type of immune reactive T cells is given in Table 9.

                  TABLE 9                                                         ______________________________________                                        Restrictions On Lymphoid Cell Activation                                          Function    Phenotype   Restriction                                       ______________________________________                                        T helper    CD4.sup.+ CD8.sup.-                                                                       Class II MHC + Antigen                                  DTH CD4.sup.+ CD8.sup.-  Class II MHC + Antigen                               CTL CD4.sup.- CD8.sup.+  or                                                    CD4.sup.+ CD8.sup.-  Class I or II MHC +                                       Antigen                                                                     Suppressor CD4.sup.- CD8.sup.+  Class I MHC                                 ______________________________________                                    

T helper cell activation and delayed hypersensitivity effector (DTH)cells are antigen and class II MHC restricted; CTL activities areantigen and class I or class II MHC restricted. Suppression can be classI restricted or unrestricted. Surface phenotype (CD4 or CD8) correlatesmainly with MHC recognition of class II (CD4⁺) or class I (CD8⁺).

Considering the important regulatory role of class II restricted inducercells (all of which are CD4⁺), it is not surprising that a virus such asthe AIDS-related virus, which infects T cells through the CD4 marker andthus selectively depletes the CD4 population, can cause the severeimmune suppression and other abnormalities of lymphocyte growth seen inAIDS patients. This invention should make it possible to inhibitinfection of cells by blocking the susceptible cell surface marker witheither the altered MHC class I or class II determinant or by thecomposition comprising antigen bound to the altered determinant. Thisinvention should also make it possible to mimic antigen binding to the Tcell receptor α- and β-chains or to the δ-chains. By cross-linkingreceptors with the altered determinant of the invention, T cellactivation is facilitated. This invention thus makes it possible tostimulate or enhance the function of the immune system.

8. Methods Of Preparing Altered MHC Class I And Class II Determinants

The altered MHC class I and class II determinants of the invention canbe prepared according to well known recombinant DNA techniques. Moreparticularly, nucleic acid sequences encoding the domains of class I andclass II MHC gene products and β₂ m, and spacers where appropriate, areemployed in this invention. A nucleic acid fragment of interest can beligated to a cloning vehicle. The nucleic acid can be obtained from anysource, for example, from plasmids, from cloned DNA or RNA, or fromnatural DNA or RNA from any source. DNA or RNA can be extracted from abiological material, such as biological fluids or tissue, by a varietyof techniques including those described by Maniatis et al., MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York(1982). The nucleic acid will generally be obtained from a higherorganism, such as an animal. The nucleic acid sequence can also bechemically synthesized using conventional techniques.

It is not necessary that the nucleic acid fragment to be ligated bepresent in a pure form. The nucleic acid to be ligated can contain morethan one specific nucleic acid sequence, which can be the same ordifferent. The specific nucleic acid fragment to be ligated can be afraction of a larger molecule or the fragment can constitute an entiregene or assembly of genes encoding the domains of interest. The DNA canbe a single-stranded or double-stranded form. If the fragment is insingle-stranded form, it can be converted to double-stranded form usingDNA polymerase according to conventional techniques.

The nucleic acid fragment to be ligated can have cohesive endscompatible with any combination of sites in a cloning vehicle.Alternatively, the nucleic acid fragment can have one or more blunt endsthat can be ligated to corresponding blunt ends in the cloning sites ofthe vehicle. The nucleic acid fragment to be ligated can be furtherprocessed, if desired, by successive exonuclease deletion, such as withthe enzyme Bal 31. In the event that the nucleic acid fragment to beligated does not contain a desired combination of cohesive ends, thefragment can be modified by adding a linker, an adaptor, or homopolymertailing.

If it is difficult to determine which fragment in a complicated mixtureof nucleic acid sequences is desired for ligation, or if it is desiredto ligate more than a single nucleic acid fragment, mixtures of nucleicacid fragments can be employed. This procedure can be utilized togenerate a small library of clones that contain all compatible fragmentsin the original nucleic acid mixture.

The cloning vehicle employed in practicing the invention can be anydouble-stranded DNA molecule capable of transporting the nucleic acidfragment to be ligated into the host cell and capable of replicatingwithin the cell. More particularly, the cloning vehicle must contain atleast one DNA sequence that can act as the origin of replication in ahost cell. In addition, the cloning vehicle must contain two or moresites for insertion of the nucleic acid sequence to be ligated. Thesesites will ordinarily correspond to restriction enzyme sites at whichcohesive ends can be formed, and which are complementary to the cohesiveends on the nucleic acid fragment to be ligated to the vehicle. Ingeneral, this invention can be carried out with plasmid, bacteriophage,or cosmid cloning vehicles having these characteristics.

It is preferred that the plasmid carry one or more genes responsible fora useful characteristic, such as selectable marker, displayed by thehost cell. In one type of strategy, plasmids having genes for resistanceto two different drugs are chosen. For example, insertion of the DNAfragment of interest into a gene for an antibiotic inactivates the geneand destroys drug resistance. The second drug resistance gene is notaffected when bacterial cells are transformed with the recombinants, andcolonies containing the gene of interest can be selected by resistanceto the second drug and susceptibility to the first drug. Preferredantibiotic markers are genes imparting chloramphenicol, ampicillin, ortetracycline resistance to the host cell.

When a plasmid is employed, the plasmid can be derived from bacteria orsome other organism or the plasmid can be synthetically prepared. Theplasmid can replicate independently of the host cell chromosome or anintegrative plasmid (episome) can be employed. The plasmid can make useof the DNA replicative enzymes of the host cell in order to replicate orthe plasmid can carry genes that code for the enzymes required forplasmid replication. A number of different plasmids can be employed inpracticing this invention. Typical of the plasmids that can be utilizedare pBR322, pBR325, Co1E1, RP4, and the 2 μm circle that occurs in manystrains of the yeast Saccharomyces cerevisiae. The cloning vehicle canalso be a bacteriophage. It will be understood that this invention canbe practiced with phage vectors that proliferate by a lytic cycle or bylysogenic infection.

Cloning can be carried in procaryotic or eucaryotic cells. The host forreplicating the cloning vehicle will of course be one that is compatiblewith the vehicle and in which the vehicle can replicate. Cloning can becarried out in bacterial or yeast cells, although cells of fungal,animal, and plant origin can also be employed. The preferred host cellsfor conducting cloning work are bacterial cells, such as E. coli, aswell as species of Streptomyces, Bacillus, and Pseudomonas. The use ofE. coli cells is particularly preferred because most cloning vehicles,such as bacterial plasmids and bacteriophages, replicate in these cells.Yeast cells can also be employed for cloning work. Also preferred arestrains of Saccharomyces cerevisiae. Animal cells, such as COS monkeycells, are preferred where post-translational processing of the alteredMHC determinant is desired. For example, the altered MHC class I andclass II determinants of the invention can be prepared in glycosylatedform in COS cells. This invention thus contemplates the preparation anduse of the altered determinants of the invention in glycosylated ornon-glycosylated form.

Expression control sequences can be included in the vector of thisinvention. These include the operator, promoter and ribosome binding andinteraction sequences (including sequences such as the Shine-Dalgarnosequences), the lactose operon of E. coli ("the lac system"), thecorresponding sequences of the tryptophan synthetase system of E. coli("the trp system"), the major operator and promoter regions of phage λ(O_(L) P_(L) and O_(R) P_(R) ^(I)), and the control region of the phagefd coat protein. DNA fragments containing these sequences can be excisedby cleavage with restriction enzymes from the DNA isolated fromtransducing phages that carry the lac or trp operons, or from the DNA ofphage λ or fd. These fragments can then be manipulated in order toobtain a limited population of molecules such that the essentialcontrolling sequences can be joined very close to, or in juxtapositionwith, the initiation codon of the coding sequence for the desired geneproduct. The product is then inserted into a cloning vehicle fortransformation of the appropriate hosts and the level of productionmeasured. Cells giving the most efficient expression can be selected.

To shorten the distance between the particular expression controlsequence and the initiation codon of the chosen gene fragment, theparticular fragment may be treated lightly with a combination ofnucleases acting specifically at or near its terminus or used inexonuclease and polymerase-linked repair reactions to remove some or allof those nucleotides of the fragment preceding the fragment's startcodon. Alternatively, a fragment can be similarly shortened withexonuclease treatment or polymerase-linked repair reactions and thencleaved to produce one fragment to permit fusion to another fragmentbefore attachment to the expression control sequence.

The nucleotide sequences encoding domains of class I and class IImammalian gene products are known in the art and can be employed inpracticing this invention. For example, following are primary structuraldata for β₂ m molecules from several different species that can beemployed in practicing this invention.

                     10        20        30        40        50                              |         |         |                                                           |         |                                                  Mouse β2mIQKTPQIQVYSRHPPENGK                                            PNILNCYVTQFHPPHIEIQMLKNGKKIPKVE                                                 - Rat β2m                       F-----S-----Q---EL--------NI-                                                   - Guinea Pig β2mVHLA-RV-------A----Q-FT----SG----Q--VEL-------DN--       - Rabbit β2mV-RA-NV-------A------F-----SG----Q-D-EL---V---EN--                                                  - Human β2m                     R--K  -------A----S-F-----SG--SD--VDL--D-ER-E---                                - Bovine β2m                                                           RP-K---------------Y-----YG----Q---DL----E--KS -                                -  -  -         60        70        80        90       99                             |         |         |                                                           |        |                                                   Mouse β2mMSDMSFSKDWSFYILAHTE                                            FTPTETDTYACRVKH SMAEPKTVYWDRDM                                                  - Rat β2m                       L----------------------V-------VTLK-----------                                  - Guinea Pig β2m                                                       L------T--L-V-AA---NDS-E-S---S-ITLS---I-K--PNK                                  - Rabbit β2mQ--L--N------L-V------NNKNE-S-----VTLK--M--K----Y                                                   - Human β2mH--L---------L-Y                                            Y-------K-E-----N-VTLSQ--I-K-----        - Bovine β2mQ--L---------L-S-A----DSK-E-S-----VTLEQ-RI------L     

The straight lines indicate homology to the sequence listed at the top.The single letter code for amino acids is used where A is Ala; C, Cys;D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met;N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; Y, Tyr.Position 85 of mouse β₂ m is Ala for C57BL/6 mice and Asp for BALB/c.Source: Paul, Fundamental Immunology, 2nd Ed., Raven Press, N.Y. (1989),page 500.

Exemplary of other sequences that can be employed in this invention arethose in the following compilation of sequences for murine class Imolecules encoded within H-2, Q, and TL subregions.

           EXON 2                                                                        1   5    10   15   20   25   30   35   40   45   50   55   60   65              70   75   80   85   90                                                 H-2K.sup.b GPHSLRYFVTAVSRPGLGEPRYMEVGYVDDTEFVRFDSDAEMPRYEPRARWMEQEGPEYWE           RETQKAKGNEQSFRVDLRTLLGYYNQSKG                                             - H-2K.sup.d                                                                FIA-------Q--------D---F----P-----------EQ--R--SD--W---S---AQR-------                 - H-2K.sup.k                                                          N---------K--FIS-------Q----------------V-----VE------N--I------I---N---A           -R-----A-                                                                 - H-2K.sup.q                                                                N------*-*K--FIS------------------------------VE------N--I--D----S-------           -R-----A-                                                                 - H-2K.sup.d                                                                S--------------F------------N---------------------I------------RR--------           ------A-R-----A-                                                          - H-2D.sup.p                                                                K----------N--------------MK--V------------Q---N--DH------S--N----------        - H-SD.sup.b                                                                H---E--------E----IS-----NK------------------P-------------------Q--W---S           --N--------A-                                                             - H-2L.sup.d                                                                H---E-------------IS-----NK----------------Q-P------------I--I---Q--W---N           -----------A-                                                             - Q-7.sup.d (27.1)                                                          Q---Q--H-----------WFIS-------Q------------M-------------------M---A-----           GS---AQS-------                                                           - Q-7.sup.b                                                                 Q---Q--H-----------WFIS-------Q------------M-------------------I---H-----           GS---AQS-------                                                           - Q-8.sup.b                                                                 H----W---V---FII-------Q------------M-----------------------H-E----S---AQ           S-------                                                                  - Q-9.sup.b                                                                 Q---Q--H-----------WFIS-------Q------------M-------------------I---H-----           GS---AQS-------                                                           - Q-10.sup.b                                                                S--M---E-S----------FII-------Q---------T--M----P--------------R--------H           -S------H----ES                                                           - PH-2.sup.d -37 S-------T------------FII-------Q------------M------I--           ---------W--ROMGRN---N-----------ND                                       - 17.3A                                                                     S------Y--L---AIS--W-IA---L---Q-A----AG-TGT-KLS-P-V-------A---EIVTS-A-F--           EN-Q-M-D---L-QN                                                           - C25.1                                                                     S------Y--L---AIS--W-IA---L---Q----N-SG-TAT-KLS-P-V-------A---EIVTS-A-F--           EN-Q-M-D---L-QN                                                           - Tla.sup.a -1                                                              S---K--Y--L---AIS--W-IAG--L---Q-RC-E-AG-SAT-KL--P-V-------A---EIVTS-A-F--           EN-Q-M-D--SL-QN                                                           -                                                                                 EXON 3                                                                        91  95   100  105  110  115  120  125  130  135  140  145  150                155  160  165  170  175  180                                             K-2K.sup.b GSHTIQVISGCEVGSDGRLLRGYQQYAYDGCDYIALNEDLKTWTAADHAALITKHKWEQAG           EAERLRAYLEGTCVEWLRRYLKNGNATLLRT                                           - H-2K.sup.d                                                                F-RMF--D----W--------F----R----------------T-----RR------D--YY------E----           -----EL--E-----                                                           - H-2K.sup.k                                                                F-RMY-------W------E-------------------------------------D---D-----------           -----QL-----P--                                                           - H-2K.sup.q                                                                RMY--D-----------E-V-----------------------------------A---R------A-----S           -H-----------                                                             - H-2D.sup.d                                                                L-WMA--D-E---------W-F------------------------Q--RR------A---D------E----           ---------------                                                           - H-2D.sup.p                                                                GMR--D----W------E-F----P-------------------Q--RR------A--T-------A------           ---EL------C-                                                             - H-2D.sup.b                                                                L-QM---DL---W------L-F--E-R-------------------Q--RR----S-A--HYK-----E----           -H-------------                                                           - H-2L.sup.d                                                                T--L-WMY--------------E-F----R-------------------Q--RR------A--YY------E-           ----H-------------                                                        - Q-7.sup.d (27.1)                                                          L-WMY--DH----------L-F--E-R--------------V----Q--RR------I--KDQ-------HQS           -----QL-KE-----                                                           - Q-7.sup.b                                                                 L-WMY--DH----------L-F--E-R--------------V----Q--RR------I--KDQ-------HQS           -----QL-KE-----                                                           - Q-8.sup.b                                                                 L-WMY--D----E------L-F--E-R-------------------Q--L-------I---D------A--QS           -----QLRKE---C-                                                           - Q-9.sup.b                                                                 L-WMY--DH----------L-F--E-R--------------V----Q--RR------I--KDQ-------H-S           -----QL-KE-----                                                           - Q-10.sup.b                                                                WMY--K------F----L------R----------------V--I--RR------A--YY-----AE-----L           ---EL-KE-----                                                             - PH-2.sup.d -37 E---L-WMY--D--P--------C-E----Q---S-----RS---H-I-SQ-S-           --S-AVD--HQQ----Q-P-----H---RL--E--Q-S                                    - 17.3A                                                                     MY----EFF-S-F-A-E-HG---Q-------------------E--RS------YT-LR-T----P-KDS-L-           --E-RKK-QEC-                                                              - C25.1                                                                     MY----EFF-S-F-A-E-HG---R----------------T--E--RS------YT-LR-T----P-KDS-L-           --E-RKK-QEC-                                                              - Tla.sup.a -1                                                              MY----SSS-N-F-A-E-HG---R-------------------E--RS------YT-LR-T----P-KDS-F-           ----RKK-QECA                                                              - Tla.sup.a -3             FSSS-S-F-A-E-HG---R--------V----------E--RS-           -----YT-LR-T----P-KDS-L---E-RKK-QEC-                                      -                                                                                 EXON 4                                                                          185  190  195  200  205  210  215  220  225  230  235  240  245             250  255  260  265  270                                                   - H-2K.sup.b DSPKAHVTHHSRPEDKVTLRCWALGFYPADITLTWQLNGEELIQDMELVETRPAGDGT           FQKWASVVVPLGKEQYYTCHVYHQGLPEPLTLRW                                        - H-2K.sup.d                                                                Y-P-SQVD------------------------D-T--------------------A---------N-----H-           K----------                                                               - H-2K.sup.k                                                                R---------------------------------T--------------------------------------           -----------                                                               - H-2K.sup.q                                                                T-----------------------------------------K-------                              - H-2D.sup.d                                                                P--------R---GD--------------------------T-E----------------------------K           -----E-E----------GKE                                                     - H-2D.sup.p                                                                P--------P-S-G---------------------------T--------------------AL--------N           -----E-E----------                                                        - H-2K.sup.b                                                                P-SKGE--------------------------T------------------------------N---R---E-           ---------                                                                 - H-2L.sup.d                                                                P-SKGE--------------------------T------------------------------N---R---E-           ---------                                                                 - Q-7.sup.d (27.1)                                                          P--------P-SYGA--------------------------T--T---------V-----------------N           -----H-E----------GRW                                                     - Q-7.sup.b                                                                 P--------P-SYGA--------------------------T------------------------------N           -----H-E----------GRW                                                     - Q-8.sup.b                                                                 P--------P-SYGA--------------------------T------------------------------N           -----H-E----------                                                        - Q-10.sup.b                                                                P--T-----PGS-GD------P-------------------T-----Q------------------------N           -------E----------                                                        - PH-2.sup.d -37                                                            P--------P-S--E--------------------------T--------------------A----------           -------E----------                                                        - 17.3A                                                                     P--T-----A---GD-------------H---------------T-----------------A----S-E--K           -------E----------                                                        - C25.1                                                                     P--T-----P---GY---------R-------------------T-----------------A---------K           -------E----------                                                        - Tla.sup.a -1                                                              P--T-----P---GY-----------------------------------------------AL---S-E--K           -------K----------                                                        - Tla.sup.a -2                 ---------------------T------------------           -------AL---S-E--K-------K----------                                      - Tla.sup.a -3                                                              P--T-----P---GY-----------------------------------------------A----S-E--K           -------E----------                                                        -                                                                                 EXON 5                   EXON 6  EXON 7  EXON 8                           275  280  285  290  295  300  305  310 315  320  325      330  335                                                                 340  345  350                                                                   - H-2K.sup.b                                                                EPPPSTVSNHATVAVLVV                                                            LGAAIVTGAVVAFVMKMR                                                            RRNT GGKGGDYALAP                                                              GSQTSDLSLPOCK                                                                 VMVHOPHSLA                                                                      - H-2K.sup.d                                                                KL-------TVII-----                                                            ------------------                                                            -S--                   VN-----                                                                       G-                                                                              - H-2K.sup.k                                                                TVII---------------------------                                               G-                                                                              - H-3K.sup.q                                                                A---TVII--------------------S------                                             - H-2D.sup.d                                                                S--KT-TVII--P-----VVIL---H-----S-----                                         S--M------                                                                      - H-2D.sup.p                                                                D-Y-VI---------VFII--------M---S--                                            T---                                                                          S-EM--R--- A.sup.9                                                              - H-2D.sup.b                                                                D-Y-VI----G----HAII---------S-----                                            S-EM--R--- A                                                                    - H-2L.sup.d                                                                D-Y-VI----G----HAII---------S-----                                            S-EM--R--- A                                                                    - Q-7.sup.d (27.1)                                                          Y-------I--V-D---VAII--------NS--X                                              - Q-7.sup.b                                                                 Y-------I--V-D---VAII--------NS--X                                              - Q-8.sup.b                                                                 N--I----V-WPSLELWWILX                                                           - Q-10.sup.b                                                                D-I-SHI-D-LWPSLXLWWYLX                                                          - PH-2.sup.d -37                                                            VII--------V-IL---------S---HI                                                V--CS--HVL                                                                    KSFQT-DWPQ- A                                                                   - 17.3A                                                                     Q-SMP-RT--RA-SS---M-IL-FMSGS--MWM-K-H                                         N-D-HTA-Y QNEREH---TSGX                                                         -                                                                          C25.1                                                                         L-QTSMP-RT--RA-SS---M-IL-FMSGS--MWM-K-H                                        H-D-NTA-Y                                                                                                            QNEREH---TPRAESEALGVEAGMKDLPSAPPLV                                            SX                                       - Tla.sup.a -1                                                              Q-SMP-RT--RA-SS---M-IL-FMSGS--MWM-K-H                                         H-D-NTA-C QNEREH---SPRAESEALGVEAGMKDLPSAPPLVSX                                  - Tla.sup.a -2                                                              Q-SMP-RT--RA-SS---M-IL-FMSGS--MWM-K-K                                         H-D-HTA-C QNEREH---SPRAESEALGVEAGLKDLPS                                         - Tla.sup.a -3                                                              Q-SMPTRTI-RA-SS---MVIL-VMRGSG-MWM-K-K                                         NRD-NTA-C QNEREH---SAGOESDALGVEAGLKELPTAPPLVPX                           

The above sequences are grouped by exon where exons 2, 3, and 4 encodethe extracellular domains, exon 5 encodes the transmembrane region, andexons 6, 7, and 8 encode the intracytoplasmic portions of the molecules.A indicates identity with the prototype; * indicates an unidentifiedresidue; and § indicates a deletion used to facilitate alignment of thesequences. Stop codons are represented by x in some sequences. Source:Paul, supra, at pages 502-503.

The deduced protein sequences for members of the HLA-A2/A28 family areshown below. Sequences designated with A2 are serologicallyindistinguishable and have been selected by functional assays. The A28family is divided into A68 and A69 specificities based on serologicdata. Paul, supra, at page 511.

    LEADER PEPTIDE                                                                         -20       -10                                                          HLA-A2.1 MAVMAPRTLVLLLSGALALTQTMA                                              - A2.4.sub.a                                                                  - A2.3                                                                        - A2(LEE)                                                                     - A2.2Y                                                                       - Av69                                                                        - Av68.2                                                                      - Av68.1                                                                      -                                                                          a.sub.1 DOMAIN                                                                               10        20        30        40        50        60                  70        80        90                                                   HLA-A2.1 GSHSMRYFFTSVSEPGRGEPRFIAVCYVDDTQFVAFDSDAASQRMEPRAPVIEQEGPEYWDGE          TRKVKAHSQTHRVDLGTLRGYYNQSEA                                                - A2.4.sub.a                                                                Y------------------------------------------------------------------------          ---------                                                                  - A2.4.sub.b                                                                  - A2.1/.3                                                                     - A2.3                                                                        - (Lee)                                                                     Y------------------------------------------------------------------------          ---------                                                                  - A2.2F                                                                     R-----------------------------------------------                                - A2.2Y                                                                     Y---------------------------------R--------------------------------------          ---------                                                                  - A2.4.sub.c                                                                Y---------------------------------R----------------------N---------------          ---------                                                                  - Av69                                                                      T----------------------------------------------------RN--N---Q---D-------          ---------                                                                  - Av68.2                                                                    T--N-------------------------------------------------RN--N---Q---D-------          ---------                                                                  - Av68.1                                                                    T----------------------------------------------------RN--N---Q---D-------          ---------                                                                  -                                                                          a.sub.2 DOMAIN                                                                               100       110       120       130       140       150                 160       170       180                                                  HLA-A2.1 GSHTVQRNYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVA          EQLRAYLECTCVEWLRRYLENGKETTLQBT                                             - A2.4.sub.a                                                                  - A2.4.sub.b                                                                C------------------------------------------------------------------------          ------------                                                               - A2.1/.3                                                                     - A2.3                                                                      I--E---W---------------------------                                             - A2(Lee)                                                                   F-------C----------------------------------------------------------------          ------------                                                               - A2.2F                                                                     L------------------------------------------------------------W-----------          ----------------                                                           - A2.2Y                                                                     L------------------------------------------------------------W-----------          ----------------                                                           - A2.4.sub.c                                                                L------------------------------------------------------------W-----------          ----------------                                                           - Av69                                                                        - Av68.2                                                                    I---------P-C------------------------------------------------W-----------          ----------------                                                           - Av68.1                                                                    I-N---------C------K-D---------------------------------------W-----------          ----------------                                                           -                                                                          a.sub.3 DOMAIN                                                                               190       200       210       220       230       240                 250       260       270                                                  HLA-A2.1 DAPKTHMTHHAVSDHEATLRCWALSPYPAEITLTWQRDGEDQTQDTELVETRFACDGTFQKWA          AVVVPSGQEQRYICHVQHEGLPKPLILRW                                              - A2.4.sub.a                                                                  - A2.4.sub.b                                                                  - A2.1/.3                                                                   E--------------------------------------                                         - A2.3                                                                        - A2(LEE)                                                                     - A2.2F                                                                       - A2.2Y                                                                       - A2.4.sub.c                                                                  - Av69                                                                        - Av68.2                                                                    V-----------------------------                                                  - Av68.1                                                                    V-----------------------------                                                  -                                                                          TRANSMEMBRANE REGION         CYTO. 1                                                                              CYTO. 2    CYTO. 3                                   280       290           320   310                                                                           330       340                          HLA-A2.1 EPSSQFTIPIVGIIACLVLFGAVITCAVVAAVHWRRKSS DRKGGSYSQAA SSDSAQGSDVS                                                   LTACK V                           - A2.4.sub.a                                                                  - A2.3                                                                        - A2(Lee)                                                                     - A2.2Y                                                                       - Av69                                                                        - Av68.1                                                                     Av68.2                                                                  

Amino acid sequences of representative class II α chains deduced fromcDNA clones are shown below. Residues identical to DRa sequence areindicated by hyphens. Numbering is in reference to the DRα sequence.Paul, supra, at page 519.

    __________________________________________________________________________    SIGNAL SEQUENCES                                                              __________________________________________________________________________    20       -10                                                                                  |         |                                   DRα         MAISGVPVLGFFIIAVLMSAQESWA                                   DQα1         -ILNKALL--ALALTTV--PCGG                                    DPα (MRPEDR)-FHIRAVI-RALSL-F-L-LRGAG-                                   DNα         --LRAGL----HTLMT-L-P--AG-                                   I-Aα         -PR-RALI--VLALTTML-LCGG                                    I-3α         --TIGAL--R--F------S-K---                                   -                                                                          α1 DOMAIN                                                                  -                                                                                              10        20        30        40        50        60               70        80                                                                              |         |         |                |         |         |         |                |                                                          DRα         IKEEHV IIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFAS       FEAQGALANIAVDKANLEIMTKRSNYTPITN                                              DQα1       ED-VAD--ASCGVNL-QFYGP--QYTHE-----Q-Y--LER---A--WP--SK-G       G-DP----R-M--A-H--N--I--Y-S-AA--                                             DPα         --AD-- STY-A-VQTHRPT-----E--E--M-Y--LD------H-----QAF-       -----G-----ILNN--NTLIQ---H-QA--                                              DNα         T-AD-MGSYGPA--QSYGA--Q-THE--EEQL-S--LK-S-A----P---D--R       -DP--G--G--AI--H-D-LVE---RSRAI-                                              I-Aα      EDDIEAD--GSYGIT--QS-GDI-QYT-E-----L-Y--LD------M-P--AQLR       R--P--G-Q---TG-H----L-----S--A--                                             I-Eα         -----T --------L--KR----------------IE-S--I------AK--       ------------------DV-KE---N--DA-                                              -                                                                          α2 DOMAIN                                                                  -                                                                                    90        100       110       120       130       140       150              160       170                                                                   |         |         |                      |         |         |         |                |         |                                           DRα    VPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDH       LFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHW                                          DQα1    EV-----FSK---T-GQ--T---LV-NIF-----I---S--QS--ED----S--SKS-       -S-F-IS--T----AOEI---K-------Q------                                         DPα    D------FPKE----GQ--T---H----F---L-----C--EL--E--A-SL----T-Y       S-H-----T-V--A--F-----------Q------                                          DNα    ---R----PK-R---GQ--I---IV-NIF---I-I------QT--E--AQ-SFYSQP--       ----------V--A------Q-------A---R--                                          I-Aα    EA-QA--FPK---L-GQ--T----V-NIF---I-I-----S-S--D--Y--S-FVNR-       YS-H-LS--T-I--DO-I---K------E--V----                                         I-Eα    -A------SR---N-G---I--------S------------R---E----------D-       ---------T-----D-F---E-D----E---R-A-                                          -                                                                                CONNECTING PEPTIDE    TRANSMEMBRANE REGION                                                                              CYTOPLASMIC REGION                                                              -     180       190                                                            200       210     220                                                            |                                                              |                                                                    |                                                                    |      |      DRα    EFDAPSPLPETTE NVVCALGLTVGLVGIIIGTIFII KGLRKSNAAERRGPL                                                           DQα1    -PEI-A-MS-L                                                    -- T-------S---M--VV--V---                                                     Q---SVG-SRHQ---                DPα    -AQE-IQM----- T-L-----VL----F-V--VL--                           S--SGHDPRAQ-T-                                                                 DNα    -LQV-I-P-DAM- TL------AI----FLV--VL-- M-TYV-SVPR                 I-Aα    -PEI-A-MS-L-- T-------S------VV------ Q---SGGTSRHP---                                                          I-Eα    --EEKTL----                                                    K-                             F------VV-I-L-M                                                               IK-R-VV---QGAL                                                               __________________________________________________________________________

Amino acid sequences of representative class II β chains deduced fromcDNA clones are shown below. Residues identical to DRβ sequence areindicated by hyphens. Numbering is in reference to the DRβ sequence.Paul, supra, at page 520.

    __________________________________________________________________________    SIGNAL SEQUENCES                                                              __________________________________________________________________________    30       -20       -10                                                                |         |         |                        DRβ       MVCLKLPGGSCMTALTVTLMVLSSPLALA                                  DQβ    MSWKKS-RI--DLRVATV-LM-AI---S--EG                                  DPβ        MV-QVSAAPRTV---AL----LTSVVQG                                  DOβ          MGSGWVPWVV--L-N-TR-O-SMTQG                                  I-Aβ         MALQIPSLLLS-AV-V-------RTEG                                 I-Eβ         MVW--RVP-VA-VILL-T---P-V--V                                  -                                                                          β1 DOMAIN                                                                   -                                                                                      10        20        30        40        50        60                 70        80        90                                                                 |         |         |                     |         |         |         |                |         |                                           DRβ GDTRPRFLWQLKFECHFFNGTERVRLLERCIYNQEESVRFDSDVGEYRAVTELGRPDAEYWNS       QKDLLEQRRAAVDTYCRHNYGVGESFTVQRR                                              DRβ1 R-SPED-VY-F-GL-Y-T-------GVT-H---R--Y--------V-----PQ---V-----       ---EV--GA--S--RV-----E-AYRGIL---                                             DPβ RA-PENY-F-GRQ--YA----Q-  F---Y---R--F---------F----------E-----       ---I--EE--VP-RM-----EL-GPM-L---                                              DOβ T-SPED-VI-A-AD-Y-T----K-QFVV-F-F-L--Y--------MFV-L-K--Q----Q---       RL----RS-Q---GV-----RL-AP---G-K                                              I-Aβ                                                                    NSERH-VA---G--Y-T---Q-I-SVN-Y---R--W---------------------------PEI--RT--E       ---V-----EGV-TH-SL--L                                                        I-Eβ R--P----EYVTS----Y---QH--F---F---R--NL---------------------N--       --PEI--DA--S---------EISDKFL-R--                                              -                                                                          β2 DOMAIN                                                                   -                                                                                 100       110       120       130       140       150       160              170       180                                                                   |         |         |         .vertline       .         |         |         |                    |         |                                                DRβ VEPKVTVYPSKTQPLQHHNLLVCSVSGFYPGSIEVRWFRNGQEEKAGVVSTGLIQNGDWTFQT       LVMLETVPRSGEVYTCQVEHPSVTSPLTVEW                                              DQβ                                                                     T--IS--R-EA-N-----I---TD---SQ-K------D---T------P--R-------I-----MT-QR-D-       ---H-----LQ--I----                                                           DPβ                                                                     Q-R-N-S---KG----------H-TD------Q----L-----T------N--R-------I-----MT-QQ-       D--------T-LD--V----                                                         DOβ                                                                     Q-E-----ER-PL-HQ----H---T-----D-KIK--L-----R---M---P-R--------V----MT-EL-       H----L-D-S-LL--VS---                                                         I-Aβ EQ-N-AISL-R-EA-N---T-----TD---AK-K----------TV--S--Q--R-------       V-----MT-HQ------H-----LK--I----                                             I-Eβ                                                                    T-----T-----E----------D----N---------K--ET-I-----VR-------------W--Q----       ---------L-D-V----                                                            -                                                                                  CONNECTING PEPTIDE                                                                              TRANSMEMBRANE REGION                                                                            CYTOPLASMIC REGION                   190 200       210 220       230                                                | |         |  |         .vertline                                               .                                    DRβ RARSESAQSKM LSGVGGFVLGLLFLGAGLFI  YFRNQKGHSGLQPTGFLS                 DQβ                                                                     Q--------                                                                     I---L--I-  RQ-SR-        -L-H                                                  DPβ K-Q-D--R--T                                                         T-A-------IIC-V-I-M  HR-SK-VQR-SA                                              DOβ                                                                     Q--YSWR--                                                                     IAA-L---I--LV-IV-  QL-A---YVRT-MS-NEVSRAVLLPQSC                                I-Aβ                                                                    Q----R---                                                                     I--C---VI---L----  RH-S---PR-PP-A-L-Q                                          I-Eβ K-Q-T---N--                                                          -------Q-E-----L--                                                         __________________________________________________________________________

It will be understood that this invention encompasses biochemicalvariants of class I and class II MHC domains. For example, following isa comparison of the polymorphic residues in DQα first domain sequences.Numbers correspond to amino acid residues. Identity with-the DR1 DQw1.1sequence is indicated by a hyphen; parentheses mark deleted amino acids;and a blank space indicates that no sequence data are available. Paul,supra, at page 524.

            11 18 25 26 34 40 41 45 47 48 50 51 52 53 54 55 61 64 66 69 75 76             80                                                                        |  |  |  |  |  |                                                        |  |                                                        |  |                                                        |  |                                                        |  |                                                        |  |                                                        |  |                                                        |  |                                                        |  |                                                        |                  DR1 DQw1.1  C  F  Y  T  E  E  R  A  R  W  E  F  S  K  F  G  G  R  M  A                                                        I  M  Y                       DR2 DQw1.2  -  -  -  -  Q  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -                                                        -  -  -                       DR2 DQwT.AZH  -  -  -  -  Q  -  -  -  -  -  -  -  -  -  -  -  -  -  -                                                         -  -  -  -                    DRw6 DQw1.18        F  -  Q  -  K  -  -  -  -  -  -  -  -  -  -  -  -                                                         -  -  -  -                    DRw6 DQw1.19        -  -  Q  -  -  -  -  -  -  -  -  -  -  -  -  -  -                                                         -  -  -  -                    DRw8 DQ1        F  -  Q  -  K  -  -  -  -  -  -  -  -  -  -  -  -  -  -                                                        -  -                         DR3 DQw2  Y  S  -  -  Q  G  -  V  C  L  V  L  R  Q  R [  ] F  T  I  L                                                         S  L  S                       DR4 DQw3.1  Y  S  -  S  -  -  -  V  Q  L  L  -  R  R  R  R  F  T  I  L                                                        -  V  S                       DR4 DQw3.2  Y  S  -  S  -  -  -  V  Q  L  L  -  R  R  R  R  F  T  I  L                                                        -  V  S                       DR5 DQw3.1  Y  S  -  -  Q  G  -  V  C  L  V  L  R  Q  R [  ] F  T  I  L                                                        S  L  S                      DR9 DQw3  Y  S  -  S  -  -  -  V  Q  L  L  -  R  R  R  R  F  T  I  L  -                                                        V  S                         DR8 DQblank  Y  S  -  -  Q  G  -  V  C  L  V  L  R  Q  R [  ] F  T  I                                                         T  -  L  S              

Similarly, following is a comparison of the polymorphic residues in DQβfirst domain sequences. Numbers correspond to amino acid residues.Identity with the DR1 DQw1.1-sequence is indicated by a hyphen, and ablank space indicates that no sequence data are available. Paul, supra,at page 525.

            3 9 13 14 26 28 30 37 38 45 46 47 52 53 55 56 57 66 67 70 71 74               75 77 84 85 86 87 89 90                                                  | |  |  |  |  |                                                                   |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                    |                                                                     DR1 DQw1.1                                                                   S Y  G  L  G                                                                   T  H  Y  V                                                                   G  V  Y  P                                                                    Q  R  P  V                                                                    E  V  G  A                                                                    S  V  R  E                                                                    V  A  Y  G                                                                    I                  DR2 DQw1.2                                                                    F  -  M  L  -  Y  -  A  -  -  -  -  -  -  -  D  -  -  -  T  E  L  T  -                                                                   -  -  F  -                                                                    -                  DR2 DQw1.12 P L  A  M  Y  -  Y  D  -  -  -  -  -  -  -  -  D  D  I  R                                                                    T  E  L  T                                                                    -  -  -  F                                                                    -  -                                                                           DR2                                                                          DQw1.AZH                                                                        -  -  -  -                                                                   -  -  -  -                                                                   -  -  -  -                                                                    -  -  -  S                                                                    -  -  -  -                                                                    -  -  -  -                                                                    -  -  -  -                                                                    -                  DRw6 DQw1.18            L  -  -  -  A  -  -  -  -  -  -  -  D  -  -  -                                                                   T  E  L  T                                                                     DRw6                                                                         DQw1.19                                                                        -  -  M  L                                                                   -  -  -  A                                                                    -  -  -  -                                                                    -  -  -  -                                                                    -  -  R  T                                                                    E  L  T  -                                                                    -  -  G  -                                                                    -                  DR3 DQw2         M  L  S  S  I  -  -  E  F  L  L  L  -  A  D  I  R  K                                                                    A  -  -  Q                                                                    L  E  L  T                                                                    T                  DR7 DQw2                                                                      -  -  M  L  S  S  I  -  -  E  F  L  L  L  -  A  D  I  R  K  A  -  -  Q                                                                   L  E  L  T                                                                    T                  DR4 DQw3.1                                                                    -  A  M  Y  -  Y  -  A  E  -  -  -  L  P  -  D  -  -  R  T  E  L  T  Q                                                                   L  E  L  T                                                                    T                  DR4 DQw3.2                                                                    -  -  M  L  -  Y  -  A  -  -  -  -  L  P  -  A  -  -  R  T  E  L  T  Q                                                                   L  E  L  T                                                                    T                  DR5 DQw3.1                                                                    -  A  M  Y  -  Y  -  A  E  -  -  -  L  P  -  D  -  -  R  T  E  L  T  Q                                                                   L  E  L  T                                                                    T                  DR9 DQw3.3                                                                    -  -  M  L  -  Y  -  A  -  -  -  -  L  P  -  D  -  -  R  T  E  L  T  Q                                                                   L  E  L  T                                                                    T                  DR8 DQblank                                                                   F  -  M  -  -  Y  -  A  -  -  -  -  L  -  L  D  D  I  E  D  -  -  T  Q                                                                   L  E  L  T                                                                    T            

Genes encoding other MHC gene products can be determined from thephysical map of the MHC gene complex for the mammalian species ofinterest.

9. Antibodies To Altered Determinants And Compositions Of The Invention

The altered MHC class I and class II determinants of the invention andcompositions containing antigens bound to the determinants are usefulfor the preparation of antibodies that recognize these substances. Theantibodies have diagnostic uses, application in mammalian therapy, anduse in the study of MHC and cellular processes.

More particularly, polyclonal or monoclonal antibodies can be used in avariety of applications. Among these the neutralization of MHC geneproducts by binding to the gene products on cell surfaces. They can alsobe used to detect MHC gene products in biological preparations or inpurifying corresponding MHC gene products or the altered MHC class I andclass II determinants of the invention, such as by affinitychromatography.

Antibodies according to the present invention can be prepared by any ofa variety of methods. For example, cells expressing an altereddeterminant or a functional derivative thereof can be administered to ananimal in order to induce the production of sera containing polyclonalantibodies that are capable of binding the altered determinant. Inaddition, antibodies can be prepared to a variety of altered MHC class Iand class II determinants of the invention and compositions containingantigens bound to the determinants in a similar manner.

In a preferred method, the antibodies are monoclonal antibodies, whichcan be prepared using hybridoma technology (Kohler et al., Nature256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler etal., Eur. J. Immunol. 6:292 (1976); Hammerling et al., In: MonoclonalAntibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)).In general, such procedures involve immunizing an animal with thealtered MHC determinant or the altered MHC-antigen composition.Splenocytes of the animals are extracted and fused with a myeloma cellline. After fusion, the resulting hybridoma cells can be selectivelymaintained in HAT medium, and then cloned by limiting dilution asdescribed by Wands, J. R., et al. Gastroenterology 80:225-232 (1981).The hybridoma cells obtained are then assayed to identify clonessecreting antibodies capable of binding the altered MHC determinant orthe composition.

See also 2,658,197 (Al) [90 01769], Feb. 14, 1990, "RestrictedMonoclonal Antibodies That Recognize A Peptide That Is Associated WithAn Antigen Of A Major Histocompatibility Complex", Use In Diagnosis andTreatment, "Huynh Thien Duc Guy", Pririe Rucay, Philippe Kourilsky;National Institute of Health and Medical Research.

The antibodies can be detectably labeled. Examples of labels that can beemployed in the present invention include, but are not limited to,enzymes, radioisotypes, fluorescent compounds, chemiluminescentcompounds, bioluminescent compounds and metal chelates.

Examples of enzymes include malate dehydrogenase, staphylococcalnuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase,alpha-glycerophosphate dehydrogenase, triose phosphate isomerase,biotin-avidin peroxidase, horseradish peroxidase, alkaline phosphatase,asparaginase, glucose oxidase, β-galactosidase, ribonuclease, urease,catalase, glucose-VI-phosphate dehydrogenase, glucoamylase andacetylcholine esterase.

Examples of isotopes are ³ H, ¹²⁵ I, ³² P ³⁵ S ¹⁴ C ⁵¹ Cr, ³⁶ Cl, ⁵⁷ Co,⁵⁸ Co, ⁵⁹ Fe, and ⁷⁵ Se. Among the most commonly used fluorescentlabeling compounds are fluoroscein, isothiocyanate, rhodamine,phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde andfluorescamine.

Examples of typical chemiluminescent labeling compounds are luminal,isoluminol, theromatic acridinium ester, imidazole, acridinium salts,oxalate ester, and dioxetane.

Those of ordinary skill in the art will know of other suitable labelsfor binding to antibodies, or will be able to ascertain the same by theuse of routine experimentation. Furthermore, the binding of these labelsto antibodies can be accomplished using standard techniques commonlyknown to those of ordinary skill in the art. Bioluminescent compoundsfor purposes of labeling include luciferin, luciferase and aequorin.

The antibodies and antigen of the present invention are ideally suitedfor the preparation of a kit. Such kit may comprise a carrier meansbeing compartmentalized to receive one or more container means, such asvials, tubes and the like, each of said container means comprising theseparate elements of the assay to be used.

10. Diagnostic Applications

The altered MHC class I and class II determinants, compositionscontaining antigens bound to the altered determinants, and antibodies tothese substances are useful in diagnostic applications. For example, thealtered determinants can be used to target lymphocyte receptors, such asCD4⁺ and CD8⁺ receptors of T lymphocytes, and the resulting bounddeterminant can be assayed, for instance, by means of an antibody to thebound determinant. In addition, it will be understood that the alteredMHC determinants of the invention can be labeled in the mannerpreviously described for antibodies. In this case, the label on thealtered MHC determinant can be detected and quantified. Compositionscomprising an antigen bound to an altered determinant of the inventioncan be used in a similar manner with MHC-restricted receptorsrecognizing the antigen and the determinant.

Typical examples of assays based on the antibodies of the invention areradioimmunoassays (RIA), enzyme immunoassays (EIA), enzyme-linkedimmunosorbent assays (ELISA), and immunometric or sandwich immunoassays,including simultaneous sandwich, forward sandwich, and reverse sandwichimmunoassays.

In the pre ferred mode for preforming the assays it is desirable toemploy blockers in the incubation medium to assure that non-specificproteins, protease, or human antibodies to immunoglobulins present inthe experimental sample do not cross-link or destroy the antibodies andyield false positive or false negative results. Nonrelevant (i.e. nonspecific) antibodies of the same class or subclass (isotype) as thoseused in the assays (e.g. IgG, IgM, etc.) can be used as blockers. Inaddition, a buffer system should be employed. Preferred buffers arethose based on weak organic acids, such as imidazole, HEPPS, MOPS, TES,ADA, ACES, HEPES, PIPES, TRIS, and the like, at physiological pH ranges.Somewhat less preferred buffers are inorganic buffers such as phosphate,borate or carbonate. Finally, known protease inhibitors can be added tothe buffer.

Well known solid phase immunoadsorbents, such as glass, polystyrene,polypropylene, dextran, nylon and other materials, in the form of tubes,beads, and microtiter plates formed from or coated with such materials,can be employed in the present invention. Immobilized antibodies can beeither covalently or physically bound to the solid phase immunoadsorbentby techniques, such as covalent bonding via an amide or ester linkage,or by adsorption.

11. Immunization and Therapeutic Administration

In another embodiment of this invention, the altered MHC class I andclass II determinants and compositions containing antigens bound to thedeterminants and antibodies to these substances can be administered to amammal to produce a therapeutic effect. For example, immune responses toself components represent a failure of immunological tolerance. As aresult, clones of T cells and B cells emerge bearing receptors forself-antigens, which can lead to the production of self-directedantibodies, cytotoxic T cells, and inflammatory T cells. Such abreakdown in tolerance produces an autoimmune response that can causeautoimmune diseases. Administration of the altered determinants,compositions, or antibodies of the invention can intervene in theseprocesses. Thus, for example, this invention can be utilized to treat Tcell mediated autoimmune diseases, such as thyroiditis and multiplesclerosis.

This invention also provides altered MHC class I and class IIdeterminants for use in therapeutic or vaccine compositions.Conventional modes of administration can be employed. For example,administration can be carried out by oral, respiratory, or parenteralroutes. Intradermal, subcutaneous, and intramuscular routes ofadministration are preferred when the vaccine is administeredparenterally.

The ability of the altered determinants and compositions of theinvention to exhibit a therapeutic or immunizing effect can be enhancedby emulsification with an adjuvant, incorporation in a liposome,coupling to a suitable carrier, or even in cells, or by combinations ofthese techniques. For example, the altered determinants and compositionscan be administered with a conventional adjuvant, such as aluminumphosphate and aluminum hydroxide gel, in an amount sufficient to mediatehumoral or cellular immune response in the host. Similarly, thesereagents can be bound to lipid membranes or incorporated in lipidmembranes to form liposomes. The use of nonpyrogenic lipids free ofnucleic acids and other extraneous matter can be employed for thispurpose.

In addition, any of the common liquid or solid vehicles can be employed,which are acceptable to the host and do not have any adverse sideeffects on the host nor any detrimental effects on the reagents of theinvention. Conveniently, phosphate buffered saline at a physiological pHcan be employed as the carrier. One or more injections may be required,particularly one or two additional booster injections. It will beunderstood that conventional adjuvants, such as SAF-1, complete Freund'sadjuvant and incomplete Freund's adjuvant, or oil-based adjuvants, suchas mineral oil, can be administered with the reagents of the inventionto elicit an increased antibody or cell-mediated immune response.

The immunization schedule will depend upon several factors, such as thesusceptibility of the host and the age of the host. A single dose of thereagents of the invention can be administered to the host or a primarycourse of immunization can be followed in which several doses atintervals of time are administered. Subsequent doses used as boosterscan be administered as needed following the primary course.

In an initial protocol, the mouse can be injected with about 10 to about20 μg of the altered MHC determinant of the invention per injection. Theusual vaccine dosages can be employed in humans.

In addition to the antibodies produced for kits and diagnostic assays,antibodies of the present invention can be humanized by procedures wellknown in the art (using either chimeric antibody production or CDRgrafting technology). U.S. Pat. No. 4,816,567 Cabilly et al., EPA0120694 Publication No., assigned to Celltech, EPA 0173494 PublicationNo. assigned to Stanford University, and EPA 0125023 Publication No.assigned to Genentech, describing chimeric antibody procedures and EPA0194276 Publication No. assigned to Celltech describing CDR graftingprocedures.

The humanized antibodies would be prepared from antibodies obtainedagainst specific MHC-antigen complexes. The humanized antibodies couldthen be used therapeutically in humans so as to avoid the problemsassociated with the use of non-human antibodies in human therapy.

This invention will now be described in greater detail in the followingExamples.

EXAMPLE I Engineering of Single-Chain Murine Class I MajorTransplantation Antigen

Single-chain mouse K^(d) molecules (SC-K^(d)) were engineered byconnecting residue 276 of K^(d) heavy chain to the first residue of β₂-microglobulin through spacers of various lengths, and expressedintracellularly in monkey COS-1 cells. Labeled SC-K^(d) molecules werefound to react with several monoclonal antibodies, which recognizenative K^(d) molecules. SC K^(d) -15 (with a spacer of 15 residues) wasstudied in more detail. It could be purified and shown to regain anative-like structure after treatment with denaturing agents. PurifiedSC-K^(d) -15 could bind certain peptides in a manner qualitativelysimilar to that of K^(d).

Plasmid constructs

A full-length K^(d) cDNA (Lalanne, J.-L., Delarbre, C., Gachelin, G.,and Kourilsky, P., Nucleic Acids Res., 1983. 11:1567) was cut by HindIII (at the level of residue 276) and fused in phase, by a Gly-Glycoding linker, to β₂ m cDNA (Daniel, F., Morello, D., LeBail, O.,Chambon, P., Cayre, Y., and Kourilsky, P., EMBO J. 1983. 2:1061) inwhich a Bam HI site overlapping the first Ile codon of mature β₂ m hadbeen introduced by site-directed mutagenesis. The block was cloned in amammalian expression vector, pKC3 (kindly provided by Dr. Hanahan,U.C.S.F.), which contains the SV40 promoter and origin of replication,yielding pSC-K^(d) -2 (shown in Gene Constructs discussion, FIG. 5A).Synthetic linkers of different lengths were then ligated at the Bam HIsite of PSC-K^(d) -2 (FIG. 5B). For example, the SC-K^(d) -15 liner was:

    (SEQ ID NO:15) 5' GATCGGATCCGGAGGCGGTGGATCCGGTGGCGGCGGTTC 3'                     - (SEQ ID NO:16) 3' CCTAGGCCTCCGCCACCTAGGCCACCGCCGCCAAGCTAG 5'         

Bam HI digestion of pSC-K^(d) -15 and religation yielded PSC-K^(d) -10.pSC-K^(d) -13, -17, -19 and -21 were obtained by cloning the appropriatelinkers into the Bam HI site of pSC-K^(d) -10. All spacers and junctionswere sequenced. Transfection and immunoprecipitation

COS-1 cells (about 3.5×10⁶ cells in 60-mm plates) grown in DMEMsupplemented with 10% newborn serum, penicillin, streptomycin andL-glutamine, were transfected one day after plating with 0.5 ml calciumphosphate mixture containing 5 μg of CsCl-purified plasmid DNA.Transfection efficiencies were occasionally monitored with pCH110plasmid expressing E. coli β-galactosidase (Pharmacia, Uppsala, Sweden).Thirty-six hours after transfection, cells were radiolabeled with [³⁵ S]methionine (45 μCi/plate=1.67 m Bq/plate) for 4 h at 37° C., then washedonce in PBS and collected in 1 ml lysis buffer (10 mM Tris-HCl, pH 7.4,1 mM EDTA, 150 mM NaCl, 1% w/v NP40, BSA 10 mg/ml) containing 20 mMiodoacetamide and 1 IU/ml aprotinin. Lysates were precleared withprotein A-Sepharose for 1 h at 4° C., and SN were incubated for 18 h at4° C. with either 30 μl of culture SN or 5 μl of purified mAb andprotein A-Sepharose. The beads were washed three times and the proteinswere eluted in Laemnli buffer with 2-ME and analyzed by SDS-PAGE on 12%gels. Gels were fixed, treated with AMPLIFY (Amersham Int., Amersham,GB), dried and visualized by autoradiography with use of Kodak(Rochester, N.Y.) XAR-X-ray film.

For endoglycosidase H (Endo H) treatments, samples were equilibrated in0.5% SDS, 1M 2-ME, boiled for 2 min., precipitated with 15%trichloroacetic, rinsed with acetone and resuspended in 50 μl 50 mMsodium citrate, pH 5.5, 0.1% SDS, 20 mM2-ME. Endo H(Boehringer-Mannheim, Mannheim, FRG) was added to a final concentrationof 150 mU/ml, samples were incubated at 37° C. for 24 h, and thenanalyzed by SDS PAGE.

Immunoaffinity purification of SC-K^(d) -15 protein

COS-1 cells (usually 10⁷ cells) were transfected with pSC-K^(d) -15 DNA,labeled and lysed as above. SN were precleared with protein A-Sepharosefor 1 h at 4° C. then incubated for 18 h at 4° C. with 100 μl mAb 34.1.2covalently bound to protein A beads. After the final wash in PBS,SC-K^(d) -15 was eluted from the matrix with an equal volume of 3Mthiocyanate for 10 min on ice. After an overnight dialysis in PBScontaining 0.1% NP40, 0.05% Tween and 0.2% BSA, SC-K^(d) -15 was used indirect binding test as below. Its purity was assessed by SDS-PAGE.

Peptides and Peptide Binding Assays

Peptides used in this study are described in Choppin et al. (Choppin,J., Martinon, F., Gomard, E., Bahraoui, E., Connan, F., Bouillot, F.,and Levy, J.-P, J. Exp. Med., 1990. 172:889 and references therein),except for HLA-Cw3 and HLA-A24 described in Maryanski, J. Ll, Pala, P.,Cerottini, J.-C, and Corradin, G., J. Exp. Med. 1988. 167:1391. Bindingassays were performed as described in Choppin, J., Martinon, F., Gomard,E., Bahraoui, E., Connan, F., Bouillot, F., and Levy, J.-P, J. Exp.Med., 1990. 172:889. DR3, DRw13, and K^(d) molecules were also purifiedand iodinated as in Choppin, J., Martinon, F., Gomard, E., Bahraoui, E.,Connan, F., Bouillot, F., and Levy, J.-P, J. Exp. Med., 1990. 172:889.

Gene Constructs

The C-terminal part of the K^(d) heavy chain truncated in the hingeregion was hooked to the N-terminal part of β₂ -microglobulin with anappropriate spacer. From the 3-D structure of K^(d)(Prochnicka-Chalufour, A., Casanova, J.-L, Kourilsky, P., and Claverie,J.-M, Res. Immunol., 1989. 140:133) modeled after the HLA-A2 structureof Bjorkmann et al. (Bjorkmann, P. J., Saper, M. A., Samraoui, B.,Bennet, W.S., Strominger, J. L., and Wiley, D. C., Nature 1987.329:506), the minimal length of a polyglycine type of spacer wasestimated to be 11 residues, starting from residue 276 in the K^(d)amino acid sequence (which allows the use of a convenient restrictionsite in the K^(d) cDNA).

Two full-length cDNA clones encoding K^(d) (Lalanne, J.-L, Delarbe, C.,Gachelin, G., and Kourilsky, P., Nucleic Acids Res., 1983. 11:1567) andβ₂ -microglobulin (Daniel, F., Morello, D., LeBail, O., Chambon, P.,Cayre, Y. and Kourilsky, P., EMBO J. 1983. 2:106) were connected bysynthetic oligonucleotides encoding the spacers. The latter weredesigned as repeats of several glycines and one serine, (see discussionPlasmid Constructs). A series of pSC-K^(d) -coding of cDNA with spacersof 2, 10, 13, 15, 17, 19 and 21 amino acid residues were thus obtained.The verified sequences are shown in FIG. 6.

Expression of SC-Kd in transfected monkey COS-1 cells

COS-1 cells (in which the recombinant plasmids replicate) weretransiently transfected for 36 h and labeled with [³⁵ ] methionine for 4h. SC-K^(d) molecules were not directly detectable by electrophoresis ofSN or cell extracts. For immunoprecipitation, mAb 34-1-2 (Ozato, L.,Mayer, N. and Sachs, D. H., Transplantation, 1982. 34:113), which reactswith native K^(d) and D^(d).

SN contained 20-50 fold less immunoprecipitable material than cellularextracts. This is not unexpected because the K^(d) heavy chain truncatedat the level of the Hind III site is not secreted by COS-1 cells(Chambon, P., D. E. A. thesis, University of Paris, 1987). In cellularextracts, bands corresponding to proteins with an apparent molecularmass of about 52 kDa were specifically precipitated, and their mobilitydecreased slightly as the length of the spacer increased (FIG. 6A,SC-K^(d) -2,-10, -13,-17,-19,-21; for SC-K^(d) -15, see FIG. 6B). Noband was seen with mock-transfected cells and 34-1-2 (FIG. 8A, lanes NTand pKC), nor with transfected cells and an irrelevant antibody (F23, 1;FIG. 6B). After the results of Townsend et al. (Townsend, A., Ohlen, C.,Bastin, J., Ljunggren, H.-G., Foster, L., and Karre, K., Nature 1989.340:443) with the RMA-S mutant cell line, whether the addition of largeamounts of an immunogenic peptide (influenza NPR⁻) was investigated andfound to have no effect (FIG. 6A and 6B). In much of the following work,SC-K^(d) -15 was arbitrarily chosen as the prototype SC-K^(d) molecule.

In separate studies using baculovirus vectors, it has been verified that34-1-2 reacts very poorly with the K^(d) heavy chain expressed in insectcells in the absence of mouse β₂ -microglobulin (about 20- to 50-foldfold less than K^(d) associated to β₂ -microglobulin). Reactivity with34-1-2 is thus a strong indication that K^(d) heavy chain is properlyassociated with β₂ -microglobulin. To probe other parts of the K^(d)molecule, other K^(d) -specific mAb (97-G and 20-8-4 (Ozato, L., Mayer,N. and Sachs, D. H., Transplantation, 1982. 34:113 and Rebai, N.,Mercier, P., Kristensen, T., Devaux, C., Malissen, B., MAwas, C., andPierres, M., Immunogenetics 1983. 17:57) were used and identical resultswere obtained. As an example, the SC-K^(d) -2 and SC-K^(d) -15 bandsprecipitated by mAb 20-8-4 are shown in FIG. 6B. The exact specificityof 97-G is not known, but the epitope recognized by 20-8-4 has beenshown to include residues 82 and 89 belonging to the first domain ofK^(d) (Abastado, J.-P., Jaulin, C., Schutze, M.-P., Langlade-Demoyen,P., Plata, F., Ozato, K., and Kourilsky, P., J. Exp. Med. 1987. 166:327.Thus, this epitope is properly folded in SC-K^(d) -2 and SC-K^(d) -15(as well as in other SC-K^(d) molecules.

The state of glycosylation of intracellular SC-K^(d) -15 was assessed bytreatment with Endo H. The molecule appears to be fully Endo H sensitive(FIG. 6C) and, after treatment, its apparent molecular mass is about 45kDa, which fits the expected molecular mass of non-glycosylated SC-K^(d)-15 devoid of its signal peptide (390 amino acids). These resultssuggest that most of the SC-K^(d) -15 molecules are found in theendoplasmic reticulum in a high-mannose form.

With all three mAb, the precipitated SC-K^(d) -2 band was always 5-10fold less intense than that obtained with SC-K^(d) molecules with longerspacers. However, the Gly-Gly spacer is unlikely to allow properassociation of β₂ -microglobulin to the heavy chain. A 12-kDa band,presumably monkey β² -microglobulin, is co-precipitated in relativelymuch higher amounts with SC-K^(d) -2 than with other SC-K^(d) (FIG. 6D).This suggests that monkey β₂ -microglobulin may associate better withSC-K^(d) -2 than with other SC-K^(d) where the longer spacer permitsproper folding of the murine β₂ -microglobulin over the K^(d) heavychain, which could explain the detection of some SC-K^(d) -2 molecules.In any case, monkey β₂ -microglobulin does not play a compulsory role inthe folding of SC-K^(d) -15 since it has been possible to produceimmunoprecipitable SCK^(d) -15 in insect cells infected by a recombinantbaculovirus.

Purification and peptide binding

The reactivity of SC-K^(d) molecules with three distinct mAb providedevidence for their native-like character Nevertheless, it was necessaryto purify these molecules, check their ability to fold back aftertreatments which separate heavy chain from β₂ m, and finally testwhether they were able to bind peptides.

A solid-phase matrix, made of 34-1-2 coupled to protein A beads, wasused to purify ³⁵ S-labeled SC-K^(d) -15 from lysates of transientlytransfected COS-1 cells. Treatment with 3M sodium thiocyanate eluted theprotein with a reasonable yield (about 70%) as assessed by a secondimmunoprecipitation with 34-1-2. After electrophoresis, the purifiedmaterial ran as a single 52-kDa band. This confirmed that reactivitywith 34-1-2 can be regained in the absence of detectable monkey β₂-microglobulin. This eluting treatment would normally dissociate heavychain from β₂ -microglobulin (Elliott, T., and Eisen, H. N., Proc. Natl.Acad. Sci., USA 1990. 87:5213). In addition 6M urea was also used withsimilar results (not shown).

K^(d) molecules isolated from the spleen of BALB/c mice were thenpurified and iodinated. They were purified by affinity chromatography ona 20-8-4 mAb column and compared binding of peptides by the latter andby ³⁵ S-labeled SC-K^(d) -15 in the assay of Bouillot et al. (Bouillot,M., Choppin, J., Cornille, F., Martinon, F., Papo, T., Gomard, E.,FournieZaluski, M.-C., and Levey, J.-P., Nature 1989. 339:473 andChoppin, J., Martinon, F., Gomard, E., Bahraoui, E., Connan, F.,Bouillot, F., and Levy, J.-P, J. Exp. Med., 1990. 172:889).

Two peptides from HIV viral proteins (env 312-327 and vpr 68-80), knownto bind strongly to several MHC molecules (Choppin, J., Martinon, F.,Gomard, E., Bahraoui, E., Connan, F., Bouillot, F., and Levy, J.-P, J.Exp. Med., 1990. 172:889), showed significant binding to SC-K^(d) -15 aswell as to the HLA-DR3 or DR213 positive control (Table 10; resultsshown in duplicate). In a separate experiment, the binding of SC-K^(d)-15) and that of conventional K^(d) were compared (Table 10). As above,peptide env 312-327 was found to bind to both molecules, but threepeptides known to be immunogenic (HLA-A24 170-182, HLA-Cw3 170-182 andinfluenza NPR- 147-158; (Maryanski, J. L., Pala, P., Cerottini, J.-C.and Corradin, G., J. Exp. Med. 1988. 167:1391 and Bodmer, H. C.,Pemberton, R. M., Rothbard, J. B., Askonas, B. A., Cell 1989. 52:253),showed no detectable binding, either to the SC-K^(d) nor to the K^(d)molecules. In a competition experiment in which the env 312-327 peptideis bound to plastic, it was seen that the vpr 68-80 peptide competedefficiently, while the Cw3 170-182 peptide (which did not bind in thedirect assay) did not. In summary, SC-K^(d) -15 bound in the HIVpeptides env 312-327 and vpr 68-80 to a significant extent, albeitsomewhat less efficiently than conventional K^(d) (but the optimalconditions may be different for K^(d) and SC-K^(d) -15 and efforts havenot been made to optimize binding to SC-K^(d) -15 at this stage).

There was no detectable binding of three immunogenic peptides neither toSC-K^(d) -15 nor to K^(d). It is possible that these peptides bind muchless efficiently than the two above-described HIV peptides and that theassay, as carried out here, is not sensitive enough to detect binding.Similar observations have been made before (Choppin, J., Martinon, F.,Gomard, E., Bahraoui, E., Connan, F., Bouillot, F., and Levy, J.-P, J.Exp. Med., 1990. 172:889).

In conclusion, not ignoring the difficulties associated with theinterpretation of such peptide binding experiments, this exampledemonstrates that the behavior of SC-K^(d) -15 is qualitatively similarto that of conventional K^(d). This is clear preliminary evidence thatSC-K^(d) 15 is capable of binding peptides in a manner similar to thatof K^(d).

In conclusion, this example demonstrates the engineering of single-chainK^(d) molecules which so far display the expected properties withrespect to (a) reactivity with three mAb, one of which probes properassociation with β₂ -microglobulin and another one an epitope belongingto the first domain, (b) efficient refolding upon treatment with 3Msodium thiocyanate or 6M urea, and (c) binding of certain peptides.Above 10 residues or so, the length of the spacer between K^(d) heavychain and murine β₂ -microglobulin does not seem critical. Allexperiments described have been performed with trace amounts ofmetabolically labeled SCK^(d) molecules. Production in large amountsshould yield material useful for peptide and TcR binding studies.

                  TABLE 10                                                        ______________________________________                                        Binding of peptides to purified MHC molecules.sup.1/                                       .sup.35 S-labeled                                                                       .sup.125 I-labeled                                       SC-Kd HLA-DR3/DRw13                                                         ______________________________________                                        (A)                                                                             Input (cpm) 10,000 200000/200000                                              nef 66-80 475 2325/1388                                                       (30 μg/ml; pH 9.6) 397 1822/1290                                           env 312-327 750  6782/19957                                                   (30 μg/ml; pH 9.6) 712  3778/22637                                         vpr 68-80 710 18582/21838                                                     (10 μg/ml; pH 5) 621 18245/20593                                         ______________________________________                                                     .sup.35 S-labeled                                                                       .sup.125 I-labeled                                       SC-Kd H-2K                                                                  ______________________________________                                        (B)                                                                             Input (cpm) 6000 100000                                                       No coated peptide 228 1471                                                     223 1595                                                                     A24 170-182 284 1060                                                          (10 μg/ml; pH 9.6) 229 1302                                                Cw3 170-182 169 1340                                                          (10 μg/ml; pH 9.6) 117 1384                                                NPR 147-158 214 1257                                                          (10 μg/ml; pH 9.6) 171 1259                                                env 312-327 390 13772                                                         (5 μg/ml; pH 9.6) 377 13764                                                env 312-327 42 359                                                            + vpr 68-80 41 409                                                            env 312-327 367 15378                                                         + Cw3 170-182 375 15835                                                     ______________________________________                                         .sup.1/ Experiments were carried out in duplicate.                       

EXAMPLE II Preparation of an HLA-β2-Microglobulin (MHC Class I) PeptideComplex

The "empty" (i.e. devoid of peptide) MHC class I molecule is produced invast amounts in the periplasm of the E. coli strain harboring therecombinant plasmid. Inclusion bodies can be isolated, washed briefly in6M urea, and then dissolved in 8M urea, or 6M urea+3M isothiocyanate.The solubilized MHC class I molecules are then mixed with a 100 fold (ormore) molar excess of a peptide specifically presented by HLA-A2 or MHCclass I, such as Influenza virus or HIV peptides described as optimalnonapeptides by Falk et al. (Nature (1991) 351, 290). The MHC class Ipeptide mixture in a dialysis bag is then dialyzed in a small volume of6M urea plus peptide, then 4M urea plus peptide, then 2M urea pluspeptide, then large volumes of buffer. The MHC class I peptide complexis then purified by conventional methods (such as those described in"Protein Purification Applications", Harris E. L. V. & Angal S. (Eds.)IRL Press, Oxford, 1990).

EXAMPLE III Immunization

For immunization, the complex is usually coupled to a protein carrier,as it is done for synthetic vaccines. Usual vaccination protocols (withseveral immunizations and a recall injection) should be used. Theantibody response should be mainly focussed on the peptide presented bythe SC-A2 molecule. In a typical experiment, mice will be injected onthe base of the tail of 100 μl of complete Freund adjuvant together with100 λ of the SC-A2 peptide complex itself coupled to a carrier such asovalbumin of KLM. Immunization is repeated once or twice, in thefollowing weeks. One month later, mice are boosted and the response istested.

EXAMPLE IV Identification and Sequencing of T-cell Region Capable ofBinding HLA-A2-β2Microglobulin

The sequences disclosed by the invention in Examples I and II providefor a method of identifying the interaction responsible for the T-cellrecognition of HLA-A₂ -β₂ -microglobulin (MHCI).

In detail, using the sequences disclosed in Examples I and II, it ispossible to isolate the proteins which bind to these sequences. This isaccomplished using one of the methods of purifying a protein which bindsto a specific DNA sequence. Such procedures are well known in the art.Preferably, a protein which binds to a specific DNA sequence can bepurified using affinity chromatography.

Specifically the amino acid sequence corresponding to the HLA-A₂ -β₂-microglobulin binding domain is immobilized on an appropriate matrix,such as Sepharose, and used as an affinity matrix for the purificationof the proteins which bind to the particular sequence (Arcangioli B, etal., Eur. J. Biochem. 179:359-364 (1989).

Preferably the DNA binding protein is extracted from human T-cells. Theprotein extract, obtained from the T cell is applied to a column whichcontains the immobilized DNA sequence of interest. Proteins which arenot capable of binding to the DNA sequence are washed off the column.Proteins which bind to the DNA sequence are removed from the columnusing a salt gradient. The proteins eluted from such a column areenriched for the proteins which bind to the specific DNA sequencesimmobilized on the matrix. The DNA binding protein can then be furtherpurified using procedures known in the art such as ion exchangechromatography, high performance liquid chromatography, and sizeexclusion chromatography.

During the purification of the DNA binding protein, the protein can beassayed using a gel retardation assay. (Garner, M. M. et al., Nucl. AcidRes. 9:3047 and Fried, M. et al., Nucl. Acid Res. 9:6506 (1981).

Once the DNA binding protein has been purified, a partial amino acidsequence can be obtained from the N-terminal of the protein.Alternatively, the protein can be tryptically mapped and the amino acidsequence at one of the fragments can be determined by one of the methodsknown in the art.

The deduced amino acid sequence can be used to generate anoligonucleotide probe. The encoding sequence can be based on codonswhich are known to be more frequently used by the organism.Alternatively, the probe can consist of a mixture of all the possiblecodon combinations which could encode the polypeptide.

A probe complementary to the amino acid sequence can be used to screeneither a cDNA or genomic library for the genomic sequences which encodethe DNA binding protein. Once the gene encoding the DNA binding proteinhas been obtained, the sequence of the DNA can be determined, the genecan be used to obtain large amounts of the protein from a recombinanthost, or the sequence can be used in mutational analysis to furtherdefine the functional regions within the protein which interacts withthe DNA.

Alternatively, proteins which bind to T-cell epitope can be isolated byidentifying a clone expressing the protein using the technique ofSouthwestern blotting (Sharp, Z. D. et al., Biochim Biophys Acta,1048:306-309 (1990), Gunther, C. V. et al., Genes Dev. 4:6657-679(1990), and Walker, M.D. et al., Nucleic Acids Res. 18:1159-1166(1990)).

In a Southwestern blot, a labeled DNA sequence is used to screen a cDNAexpression library whose expressed proteins have been immobilized on afilter via colony or plaque transfer. The labeled DNA sequences willbind to colonies or plaques which express a protein capable of bindingto the particular DNA sequence. Clones expressing a protein which bindsto the labeled DNA sequence can be purified and the cDNA insert whichencodes the DNA binding protein can be isolated sequenced. The isolatedDNA can be used to express large amounts of the protein for furtherpurification and study, used in isolating the genomic sequencescorresponding to the cDNA, or used to generate functional derivative ofthe binding protein.

While this invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within the art to which the inventionpertains and as may be applied to the essential features hereinbeforeset forth as follows in the scope of the appended claims.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                   - -  - - (1) GENERAL INFORMATION:                                             - -    (iii) NUMBER OF SEQUENCES: 148                                         - -  - - (2) INFORMATION FOR SEQ ID NO:1:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                               - - AAGCTGGGGG GGATCCAG             - #                  - #                      - #  18                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:2:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                               - -      Lys Leu Gly Gly Ile Gln                                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:3:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 42 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                               - - AAGCTGGGGG GGATCGGATC CGGTGGCGGC GGTTCGATCC AG    - #                      - #  42                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:4:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                               - -      Gly Gly Ile Gly Ser Gly Gly Gly - # Gly Ser                              1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:5:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                               - - AAGCTGGGGG GGATCGGATC AGGCGGATCC GGTGGCGGCG GTTCGATCCA G - #                 51                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:6:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                               - -      Gly Gly Ile Gly Ser Gly Gly Ser - # Gly Gly Gly Gly Ser                  1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:7:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 57 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                               - - AAGCTGGGGG GGATCGGATC CGGAGGCGGT GGATCCGGTG GCGGCGGTTC GA - #TCCAG            57                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:8:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                               - -      Gly Gly Ile Gly Ser Gly Gly Gly - # Gly Ser Gly Gly Gly Gly        Ser                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:9:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 63 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                               - - AAGCTGGGGG GGATCGGATC AGGCTCTGGA GGTGGCGGAT CCGGTGGCGG CG -            #GTTCGATC     60                                                                 - - CAG                  - #                  - #                  - #                 63                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:10:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                              - -      Gly Gly Ile Gly Ser Gly Ser Gly - # Gly Gly Gly Ser Gly Gly        Gly Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ser                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:11:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 69 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                              - - AAGCTGGGGG GGATCGGATC AGGTGGAGGA TCTGGAGGTG GCGGATCCGG TG -            #GCGGCGGT     60                                                                 - - TCGATCCAG                - #                  - #                      - #         69                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:12:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                              - -      Gly Gly Ile Gly Ser Gly Gly Gly - # Ser Gly Gly Gly Gly Ser        Gly Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Gly Gly Ser                                                          - -  - - (2) INFORMATION FOR SEQ ID NO:13:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 75 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                              - - AAGCTGGGGG GGATCGGATC AGGCGGAGGT GGAGGATCTG GAGGTGGCGG AT -            #CCGGTGGC     60                                                                 - - GGCGGTTCGA TCCAG              - #                  - #                      - #    75                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:14:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                              - -      Gly Gly Ile Gly Ser Gly Gly Gly - # Gly Gly Ser Gly Gly Gly        Gly Ser                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Gly Gly Gly Gly Ser                                                                  20                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:15:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 39 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                              - - GATCGGATCC GGAGGCGGTG GATCCGGTGG CGGCGGTTC      - #                      - #    39                                                                     - -  - - (2) INFORMATION FOR SEQ ID NO:16:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 39 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                              - - GATCGAACCG CCGCCACCGG ATCCACCGCC TCCGGATCC      - #                      - #    39                                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:17:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 45 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA (genomic)                                     - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..45                                                  - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                              - - GGT GGC GGT GGA TCA GGC GGT GGT GGG TCG GG - #T GGC GGC GGA TCC               - #45                                                                    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gl - #y Gly Gly Gly Ser                 1               5 - #                 10 - #                 15              - -  - - (2) INFORMATION FOR SEQ ID NO:18:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                              - -      Gly Gly Gly Gly Ser Gly Gly Gly - # Gly Ser Gly Gly Gly Gly        Ser                                                                                   1            - #   5               - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:19:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                              - -      Lys Gly Ile Leu Gly Phe Val Phe - # Thr Leu Thr Val                      1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:20:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                              - -      Tyr Lys Gly Ile Leu Gly Phe Val - # Phe Thr Leu Thr Val                 1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:21:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                              - -      Thr Tyr Gln Arg Thr Arg Ala Leu - # Val Thr Gly                          1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:22:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                              - -      Ser Ala Ala Phe Glu Asp Leu Arg - # Val Leu Ser Phe Ile Arg        Gly Tyr                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:23:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                              - -      His Asn Thr Asn Gly Val Thr Ala - # Ala Cys Ser His Glu                 1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:24:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 25 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                              - -      Cys Pro Lys Tyr Val Lys Gln Asn - # Thr Leu Lys Leu Ala Thr        Gly Met                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Arg Asn Val Pro Glu Lys Gln Thr - # Arg                                              20 - #                 25                                     - -  - - (2) INFORMATION FOR SEQ ID NO:25:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                              - -      Asn Thr Asp Gly Ser Thr Asp Tyr - # Gly Ile Leu Gln Ile Asn       Ser Arg                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:26:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                              - -      Leu Glu Asp Ala Arg Arg Leu Lys - # Ala Ile Tyr Glu Lys Lys       Lys                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:27:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                              - -      Arg Tyr Leu Glu Asn Gly Lys Glu - # Thr Leu Gln Arg Thr Asp       Ala Pro                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:28:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                              - -      Leu Glu Thr Ser Glu Gly Cys Arg - # Gln Ile Leu Gly Gln Leu       Gln                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:29:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                              - -      Glu Thr Ile Asn Glu Glu Ala Ala - # Glu Trp Asp Arg Val His       Pro                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:30:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                              - -      His Ala Gly Pro Ile Ala Pro Gly - # Gln Met Arg Glu Pro Arg       Gly                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:31:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                              - -      Lys Arg Trp Ile Ile Leu Gly Leu - # Asn Lys Ile Val Arg Met       Tyr                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:32:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                              - -      Met Gln Arg Gly Asn Phe Arg Asn - # Gln Arg Lys Ile Val Lys             1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:33:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                              - -      Lys Glu Gly His Gln Met Lys Asp - # Cys Thr Glu Arg Gln Ala        Asn Phe                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:34:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                              - -      His Glu Asp Ile Ile Ser Leu Trp - # Asp Gln Ser Leu Lys                 1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:35:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                              - -      Ile Arg Ile Gln Arg Gly Pro Gly - # Arg Ala Phe Val Thr Ile        Gly Lys                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:36:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                              - -      Phe Ile Asn Met Trp Gln Glu Val - # Gly Lys Ala Met Tyr Ala       Pro Pro                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ile Ser                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:37:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                              - -      Arg Pro Gly Gly Gly Asp Met Arg - # Asp Asn Trp Arg Ser Glu       Leu Tyr                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:38:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                              - -      Val Val Gln Arg Glu Lys Arg Ala - # Val Gly Ile Gly                      1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:39:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                              - -      Arg Ile Leu Ala Val Glu Arg Tyr - # Leu Lys Asp Gln Gln Leu       Leu Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ile Trp Gly Cys Ser                                                                  20                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:40:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                              - -      Tyr Val Ala Glu Gly Thr Asp Arg - # Val Ile Glu Val Val Gln       Gly Ala                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Cys Arg                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:41:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                              - -      Arg His Ile Pro Arg Arg Ile Arg - # Gln Gly Leu Glu Arg Ile       Leu                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:42:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                              - -      Val Gly Phe Pro Val Thr Pro Gln - # Val Pro Leu Arg Pro Met       Thr                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:43:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                              - -      Met Thr Tyr Lys Ala Ala Val Asp - # Leu Ser His Phe Leu Lys       Glu Lys                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:44:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                              - -      Trp Ile Tyr His Thr Gln Gly Tyr - # Phe Pro Asp Trp Gln Asn       Tyr Thr                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:45:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                              - -      Gly Val Arg Tyr Pro Leu Thr Phe - # Gly Trp Cys Tyr Lys Leu       Val Pro                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:46:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                              - -      Leu Thr Phe Gly Trp Cys Tyr Lys - # Leu                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:47:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                              - -      Glu Asn Thr Ser Leu Leu His Pro - # Val Ser Leu His Gly Met       Asp                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:48:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                              - -      Met Glu Asn Arg Trp Gln Val Met - # Ile Val Trp Gln Val Asp       Arg                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:49:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                              - -      Val Lys His His Met Tyr Val Ser - # Gly Lys Ala Arg Gly Trp       Phe Tyr                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:50:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                              - -      Ser Pro His Pro Arg Ile Ser Ser - # Glu Val His Ile Pro Leu       Gly                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:51:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                              - -      Gly Asp Ala Arg Leu Val Ile Thr - # Thr Tyr Trp Gly Leu                 1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:52:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                              - -      Gly Leu His Thr Gly Glu Arg Asp - # Trp His Leu Gly Gln Gly        Val                                                                                  1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:53:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                              - -      Met Ala Gly Arg Ser Gly Asp Ser - # Asp Glu Asp Leu Leu Lys       Ala Val                                                                              1             - #  5                - #   10               - #         15                                                                               - -  - - (2) INFORMATION FOR SEQ ID NO:54:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                              - -      Leu Ile Lys Phe Leu Tyr Gln Ser - # Asn Pro Pro Pro Asn                 1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:55:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                              - -      Ala Arg Arg Asn Arg Arg Arg Arg - # Trp Arg Glu Arg Gln Arg              1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:56:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                              - -      Met Glu Gln Ala Pro Glu Asp Gln - # Gly Pro Gln Arg Glu Pro              1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:57:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                              - -      Ala Gly Val Ala Glu Ile Ile Arg - # Ile Leu Gln Gln Leu Leu              1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:58:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 13 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                              - -      Leu Phe Ile His Phe Arg Ile Gly - # Cys Arg His Ser Arg                  1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:59:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 98 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                              - -      Ile Gln Lys Thr Pro Gln Ile Gln - # Val Tyr Ser Arg His Pro        Pro Glu                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Asn Gly Lys Pro Asn Ile Leu Asn - # Cys Tyr Val Thr Gln Phe       His Pro                                                                                          20 - #                 25 - #                 30             - -      Pro His Ile Glu Ile Gln Met Leu - # Lys Asn Gly Lys Lys Ile        Pro Lys                                                                                      35     - #             40     - #             45                  - -      Val Glu Met Ser Asp Met Ser Phe - # Ser Lys Asp Trp Ser Phe       Tyr Ile                                                                                  50         - #         55         - #         60                      - -      Leu Ala His Thr Glu Phe Thr Pro - # Thr Glu Thr Asp Thr Tyr       Ala Cys                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Arg Val Lys His Ser Met Ala Glu - # Pro Lys Thr Val Tyr Trp        Asp Arg                                                                                           - #   85               - #   90               - #         95                                                                               - -      Asp Met                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:60:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 99 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                              - -      Ile Gln Lys Thr Pro Gln Ile Gln - # Val Tyr Ser Arg His Pro       Pro Glu                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Asn Gly Lys Pro Asn Phe Leu Asn - # Cys Tyr Val Ser Gln Phe       His Pro                                                                                          20 - #                 25 - #                 30             - -      Pro Gln Ile Glu Ile Glu Leu Leu - # Lys Asn Gly Lys Lys Ile        Pro Asn                                                                                      35     - #             40     - #             45                  - -      Ile Glu Met Ser Asp Leu Ser Phe - # Ser Lys Asp Trp Ser Phe       Tyr Ile                                                                                  50         - #         55         - #         60                      - -      Leu Ala His Thr Glu Phe Thr Pro - # Thr Glu Thr Asp Val Tyr       Ala Cys                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Arg Val Lys His Val Thr Leu Lys - # Glu Pro Lys Thr Val Tyr        Trp Asp                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Asp Met                                                          - -  - - (2) INFORMATION FOR SEQ ID NO:61:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 99 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                              - -      Val His Leu Ala Pro Arg Val Gln - # Val Tyr Ser Arg His Pro       Ala Glu                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Asn Gly Lys Gln Asn Phe Ile Asn - # Cys Tyr Val Ser Gly Phe       His Pro                                                                                          20 - #                 25 - #                 30             - -      Pro Gln Ile Glu Val Glu Leu Leu - # Lys Asn Gly Lys Lys Ile        Asp Asn                                                                                      35     - #             40     - #             45                  - -      Val Glu Met Ser Asp Leu Ser Phe - # Ser Lys Asp Trp Thr Phe       Tyr Leu                                                                                  50         - #         55         - #         60                      - -      Leu Val His Ala Ala Phe Thr Pro - # Asn Asp Ser Asp Glu Tyr       Ser Cys                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Arg Val Ser His Ile Thr Leu Ser - # Glu Pro Lys Ile Val Lys        Trp Asp                                                                                           - #   85               - #   90               - #         95                                                                               - -      Pro Asn Lys                                                          - -  - - (2) INFORMATION FOR SEQ ID NO:62:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 99 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                              - -      Val Gln Arg Ala Pro Asn Val Gln - # Val Tyr Ser Arg His Pro       Ala Glu                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Asn Gly Lys Pro Asn Phe Leu Asn - # Cys Tyr Val Ser Gly Phe       His Pro                                                                                          20 - #                 25 - #                 30             - -      Pro Gln Ile Asp Ile Glu Leu Leu - # Lys Asn Val Lys Lys Ile        Glu Asn                                                                                      35     - #             40     - #             45                  - -      Val Glu Gln Ser Asp Leu Ser Phe - # Asn Lys Asp Trp Thr Phe       Tyr Leu                                                                                  50         - #         55         - #         60                      - -      Leu Val His Thr Glu Phe Thr Pro - # Asn Asn Lys Asn Glu Tyr       Ser Cys                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Arg Val Lys His Val Thr Leu Lys - # Glu Pro Met Thr Val Lys        Trp Asp                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Asp Tyr                                                          - -  - - (2) INFORMATION FOR SEQ ID NO:63:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 100 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 7                                                               (D) OTHER INFORMATION: - #/note= "Xaa is an unidentifed amino                     acid resi - #due."                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                              - -      Ile Gln Arg Thr Pro Lys Xaa Gln - # Val Tyr Ser Arg His Pro        Pro Ala                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Asn Gly Lys Pro Ser Ile Phe Asn - # Cys Tyr Val Thr Ser Gly       His Pro                                                                                          20 - #                 25 - #                 30             - -      Ser Asp Ile Glu Ile Val Asp Leu - # Leu Lys Asp Gly Glu Arg        Ile Glu                                                                                      35     - #             40     - #             45                  - -      Lys Val Glu His Ser Asp Leu Ser - # Phe Ser Lys Asp Trp Ser       Phe Tyr                                                                                  50         - #         55         - #         60                      - -      Leu Leu Tyr Tyr Thr Glu Phe Thr - # Pro Thr Glu Lys Asp Glu       Tyr Ala                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Cys Arg Val Asn His Val Thr Leu - # Ser Gln Pro Lys Ile Val        Lys Trp                                                                                           - #   85               - #   90               - #         95                                                                               - -      Asp Arg Asp Met                                                                      100                                                           - -  - - (2) INFORMATION FOR SEQ ID NO:64:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 99 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                              - -      Ile Gln Arg Pro Pro Lys Ile Gln - # Val Tyr Ser Arg His Pro       Pro Glu                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Asn Gly Lys Pro Asn Tyr Leu Asn - # Cys Tyr Val Tyr Gly Phe       His Pro                                                                                          20 - #                 25 - #                 30             - -      Pro Gln Ile Glu Ile Asp Leu Leu - # Lys Asn Gly Glu Lys Ile        Lys Ser                                                                                      35     - #             40     - #             45                  - -      Val Glu Gln Ser Asp Leu Ser Phe - # Ser Lys Asp Trp Ser Phe       Tyr Leu                                                                                  50         - #         55         - #         60                      - -      Leu Ser His Ala Glu Phe Thr Pro - # Asp Ser Lys Asp Glu Tyr       Ser Cys                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Arg Val Lys His Val Thr Leu Glu - # Gln Pro Arg Ile Val Tyr        Trp Asp                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Asp Leu                                                          - -  - - (2) INFORMATION FOR SEQ ID NO:65:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 350 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 326..327                                                        (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                              - -      Gly Pro His Ser Leu Arg Tyr Phe - # Val Thr Ala Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Arg Tyr Met Glu - # Val Gly Tyr Val Asp Asp       Thr Glu                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Tyr Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Lys Ala Lys Gly Asn Glu Gln - # Ser Phe Arg Val Asp Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Leu Gly Tyr Tyr Asn Gln Ser - # Lys Gly Gly Ser His Thr        Ile Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Val Ile Ser Gly Cys Glu Val Gly - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Gln Gln Tyr Ala Tyr Asp Gly - # Cys Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Leu Ile       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Gln Ala Gly Glu - # Ala Glu Arg Leu Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Lys Asn        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Leu Arg Thr Asp Ser - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Ser Arg Pro Glu Asp Lys Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Ile Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Tyr                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Gln - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Val Ser Asn Met Ala Thr        Val Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Ala - # Ile Val Thr Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met Lys Met Arg Arg Arg - # Asn Thr Gly Gly Lys Gly       Gly Asp                                                                              305             - #    310             - #    315             - #        320                                                                           - -      Tyr Ala Leu Ala Pro Xaa Xaa Gly - # Ser Gln Thr Ser Asp Leu        Ser Leu                                                                                           - #   325              - #   330              - #         335                                                                              - -      Pro Asp Cys Lys Val Met Val His - # Asp Pro His Ser Leu Ala                         340 - #                345 - #                350             - -  - - (2) INFORMATION FOR SEQ ID NO:66:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 310 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                              - -      Gly Pro His Ser Leu Arg Tyr Phe - # Val Thr Ala Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Arg Phe Ile Ala - # Val Gly Tyr Val Asp Thr       Gln Phe                                                                                          20 - #                 25 - #                 30             - -      Val Arg Phe Asp Ser Asp Ala Asp - # Asn Pro Arg Phe Glu Pro        Arg Ala                                                                                      35     - #             40     - #             45                  - -      Pro Trp Met Glu Gln Glu Gly Pro - # Glu Tyr Trp Glu Glu Gln       Thr Gln                                                                                  50         - #         55         - #         60                      - -      Arg Ala Lys Ser Asp Glu Gln Trp - # Phe Arg Val Ser Leu Arg       Thr Ala                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Gln Arg Tyr Tyr Asn Gln Ser Lys - # Gly Gly Ser His Thr Phe        Gln Arg                                                                                           - #   85               - #   90               - #         95                                                                               - -      Met Phe Gly Cys Asp Val Gly Ser - # Asp Trp Arg Leu Leu Arg       Gly Tyr                                                                                          100 - #                105 - #                110            - -      Gln Gln Phe Ala Tyr Asp Gly Arg - # Asp Tyr Ile Ala Leu Met        Glu Asp                                                                                      115     - #            120     - #            125                 - -      Leu Lys Thr Trp Thr Ala Ala Asp - # Thr Ala Ala Leu Ile Thr       Arg Arg                                                                                  130         - #        135         - #        140                     - -      Lys Trp Glu Gln Ala Gly Asp Ala - # Glu Tyr Tyr Arg Ala Tyr       Leu Glu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Gly Glu Cys Val Glu Trp Leu Arg - # Arg Tyr Leu Glu Leu Gly        Asn Glu                                                                                           - #   165              - #   170              - #         175                                                                              - -      Thr Leu Leu Arg Thr Asp Ser Pro - # Lys Ala His Val Thr Tyr       His Pro                                                                                          180 - #                185 - #                190            - -      Arg Ser Gln Val Asp Val Thr Leu - # Arg Cys Trp Ala Leu Gly        Phe Tyr                                                                                      195     - #            200     - #            205                 - -      Pro Ala Asp Ile Thr Leu Thr Trp - # Gln Leu Asn Gly Glu Asp       Leu Thr                                                                                  210         - #        215         - #        220                     - -      Gln Asp Met Glu Leu Val Glu Thr - # Arg Pro Ala Gly Asp Gly       Thr Phe                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Gln Lys Trp Ala Ala Val Val Val - # Pro Leu Gly Lys Glu Gln        Asn Tyr                                                                                           - #   245              - #   250              - #         255                                                                              - -      Thr Cys His Val His His Lys Gly - # Leu Pro Glu Pro Leu Thr       Leu Arg                                                                                          260 - #                265 - #                270            - -      Trp Lys Leu Pro Pro Ser Thr Val - # Ser Asn Thr Val Ile Ile        Ala Val                                                                                      275     - #            280     - #            285                 - -      Leu Val Val Leu Gly Ala Ala Ile - # Val Thr Gly Ala Val Val       Ala Phe                                                                                  290         - #        295         - #        300                     - -      Val Met Lys Met Arg Arg                                                  305             - #    310                                                - -  - - (2) INFORMATION FOR SEQ ID NO:67:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 350 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 326..327                                                        (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                              - -      Gly Pro His Ser Leu Arg Tyr Phe - # His Thr Ala Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Lys Pro Arg Phe Ile Ser - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Tyr Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Val Arg Trp Met Glu Gln Val Glu - # Pro Glu Tyr Trp Glu Arg       Met Thr                                                                                  50         - #         55         - #         60                      - -      Gln Ile Ala Lys Gly Asn Glu Gln - # Ile Phe Arg Val Asn Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala Leu Arg Tyr Tyr Asn Gln Ser - # Ala Gly Gly Ser His Thr        Phe Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Met Phe Tyr Cys Glu Val Gly - # Ser Asp Trp Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Glu Gln Tyr Ala Tyr Asp Gly - # Cys Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Leu Ile       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Gln Ala Gly Asp - # Ala Glu Arg Asp Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Gln Leu        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Pro Arg Thr Asp Ser - # Pro Lys Ala His Val Thr       Arg His                                                                                          180 - #                185 - #                190            - -      Ser Arg Pro Glu Asp Lys Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Tyr                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Gln - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Val Ser Asn Thr Val Ile        Ile Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Ala - # Ile Val Thr Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met Lys Met Arg Arg Arg - # Asn Thr Gly Gly Lys Gly       Gly Asp                                                                              305             - #    310             - #    315             - #        320                                                                           - -      Tyr Ala Leu Ala Pro Xaa Xaa Gly - # Ser Gln Thr Ser Asp Leu        Ser Leu                                                                                           - #   325              - #   330              - #         335                                                                              - -      Pro Asp Cys Lys Val Met Val His - # Asp Pro His Ser Leu Ala                         340 - #                345 - #                350             - -  - - (2) INFORMATION FOR SEQ ID NO:68:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 307 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 16                                                              (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 18                                                              (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                              - -      Gly Pro His Ser Leu Arg Tyr Phe - # His Thr Ala Val Ser Arg        Pro Xaa                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Xaa Lys Pro Arg Phe Ile Ser - # Val Gly Tyr Val Asp Asp       Thr Glu                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Tyr Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Met Glu Gln Val Glu - # Pro Glu Tyr Trp Glu Arg       Asn Thr                                                                                  50         - #         55         - #         60                      - -      Gln Ile Ala Lys Asp Asn Glu Gln - # Ser Ser Arg Val Asp Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Leu Arg Tyr Tyr Asn Gln Ser - # Ala Gly Gly Ser His Thr        Ile Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Met Tyr Gly Cys Asp Val Gly - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Glu Gln Val Ala Tyr Asp Gly - # Cys Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Leu Ile       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Gln Ala Gly Ala - # Ala Glu Arg Arg Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Ala Cys Val Glu Trp Leu - # Ser Arg His Leu Lys Asn        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Leu Arg Thr Asp Ser - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Ser Arg Pro Glu Asp Lys Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Tyr                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Gln - # Gly Leu Pro Lys Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Ala - # Val Ser Asn Thr Val Ile        Ile Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Ala - # Ile Val Thr Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met                                                              305                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:69:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 311 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                              - -      Gly Ser His Ser Leu Arg Tyr Phe - # Val Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Phe Gly Glu Pro Arg Tyr Met Glu - # Val Gly Tyr Val Asp Asn       Thr Glu                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Tyr Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Ile Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Arg Arg Ala Lys Gly Asn Glu Gln - # Ser Phe Arg Val Asp Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala Leu Arg Tyr Tyr Asn Gln Ser - # Ala Gly Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Ala Gly Cys Asp Val Glu - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Trp Gln Phe Ala Tyr Asp Gly - # Cys Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ala - # Ala Glu Arg Asp Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Glu Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Lys Asn        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Leu Arg Thr Asp Pro - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Arg Arg Pro Glu Gly Asp Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Glu Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Lys                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Glu His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Gly Lys Glu Glu Pro Pro - # Ser Ser Thr Lys Thr Asn        Thr Val                                                                                      275     - #            280     - #            285                 - -      Ile Ile Ala Val Pro Val Val Leu - # Gly Ala Val Val Ile Leu       Gly Ala                                                                                  290         - #        295         - #        300                     - -      Val Met Ala Phe Val Met Lys                                              305             - #    310                                                - -  - - (2) INFORMATION FOR SEQ ID NO:70:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 311 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                              - -      Gly Pro His Ser Leu Arg Tyr Phe - # Val Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Lys Pro Arg Tyr Met Glu - # Val Gly Tyr Val Asp Asn       Thr Glu                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Met Lys        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Val Arg Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Gln       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Asn Ala Lys Asp His Glu Gln - # Ser Phe Arg Val Ser Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Asn Leu Gly Tyr Tyr Asn Gln Ser - # Lys Gly Gly Ser His Thr        Ile Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Gly Met Arg Gly Cys Asp Val Gly - # Ser Asp Trp Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Glu Gln Phe Ala Tyr Asp Gly - # Pro Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ala - # Ala Glu Thr Leu Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Ala Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Glu Leu        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Leu Cys Thr Asp Pro - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Ser Glu Gly Lys Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Leu Val - # Val Pro Leu Gly Lys Glu        Gln Asn                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Glu His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Asp Ser Tyr Met Val Ile        Val Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Val - # Phe Ile Ile Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met Met Met Arg Arg                                              305             - #    310                                                - -  - - (2) INFORMATION FOR SEQ ID NO:71:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 308 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                              - -      Gly Pro His Ser Met Arg Tyr Phe - # Glu Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Glu Glu Pro Arg Tyr Ile Ser - # Val Gly Tyr Val Asp Asn       Lys Glu                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Tyr Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Lys Ala Lys Gly Gln Glu Gln - # Trp Phe Arg Val Ser Leu       Arg Asn                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Leu Gly Tyr Tyr Asn Gln Ser - # Ala Gly Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Gln Met Ser Gly Cys Asp Leu Gly - # Ser Asp Trp Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Leu Gln Phe Ala Tyr Glu Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ser Gly Ala - # Ala Glu His Tyr Lys Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Glu Cys Val Glu Trp Leu - # His Arg Tyr Leu Lys Asn        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Leu Arg Thr Asp Ser - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Ser Lys Gly Glu Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Asn                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys Arg Val Tyr His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Asp Ser Tyr Met Val Ile        Val Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Met - # Ala Ile Ile Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met Lys                                                          305                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:72:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 308 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                              - -      Gly Pro His Ser Met Arg Tyr Phe - # Glu Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Arg Tyr Ile Ser - # Val Gly Tyr Val Asn Lys       Thr Glu                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Tyr Glu        Pro Gln                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Ile Thr                                                                                  50         - #         55         - #         60                      - -      Gln Ile Ala Lys Gly Gln Glu Gln - # Trp Phe Arg Val Asn Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Leu Gly Tyr Tyr Asn Gln Ser - # Ala Gly Gly Thr His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Asp Val Gly - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Glu Gln Phe Ala Tyr Asp Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ala - # Ala Glu Tyr Tyr Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Glu Cys Val Glu Trp Leu - # His Arg Tyr Leu Lys Asn        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Ala Thr Leu Leu Arg Thr Asp Ser - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Ser Lys Gly Glu Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Asn                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys Arg Val Tyr His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Asp Ser Tyr Met Val Ile        Val Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Met - # Ala Ile Ile Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met Lys                                                          305                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:73:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 311 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                              - -      Gly Gln His Ser Leu Gln Tyr Phe - # His Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Trp Phe Ile Ser - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Met Ala Lys Gly His Glu Gln - # Ser Phe Arg Gly Ser Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala Gln Ser Tyr Tyr Asn Gln Ser - # Lys Gly Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Asp Met Gly - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Leu Gln Phe Ala Tyr Glu Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Val - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ile - # Ala Glu Lys Asp Gln Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Met Gln Ser Leu - # Arg Arg Tyr Leu Gln Leu        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Leu Arg Thr Asp Pro - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Ser Tyr Gly Ala Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Ala Gly Val       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Asn                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Asn His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Gly Arg Trp Glu Pro Pro - # Pro Tyr Thr Val Ser Asn        Met Ala                                                                                      275     - #            280     - #            285                 - -      Thr Ile Ala Val Val Val Asp Leu - # Gly Ala Val Ala Ile Ile       Gly Ala                                                                                  290         - #        295         - #        300                     - -      Val Val Ala Phe Val Met Asn                                              305             - #    310                                                - -  - - (2) INFORMATION FOR SEQ ID NO:74:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 310 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                              - -      Gly Gln His Ser Leu Gln Tyr Phe - # His Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Trp Phe Ile Ser - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Ile Ala Lys Gly His Glu Gln - # Ser Phe Arg Gly Ser Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala Gln Ser Tyr Tyr Asn Gln Ser - # Lys Gly Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Asp Met Gly - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Leu Gln Phe Ala Tyr Glu Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Val - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ile - # Ala Glu Lys Asp Gln Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Met Asp Ser Leu - # Arg Arg Tyr Leu Gln Leu        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Leu Arg Thr Asp Pro - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Ser Tyr Gly Ala Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Asn                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Asn His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Gly Arg Trp Glu Pro Pro - # Pro Tyr Thr Val Ser Asn        Met Ala                                                                                      275     - #            280     - #            285                 - -      Thr Ile Ala Val Val Val Leu Gly - # Ala Val Ala Ile Ile Gly       Ala Val                                                                                  290         - #        295         - #        300                     - -      Val Ala Phe Val Met Asn                                                  305             - #    310                                                - -  - - (2) INFORMATION FOR SEQ ID NO:75:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 306 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                              - -      Gly Pro His Ser Leu Arg Tyr Phe - # His Thr Ala Val Ser Trp       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Val Glu Pro Arg Phe Ile Ile - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Lys Ala Lys Gly His Glu Glu - # Ser Phe Arg Val Ser Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala Gln Arg Tyr Tyr Asn Gln Ser - # Lys Gly Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Asp Val Gly - # Ser Asp Glu Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Leu Gln Phe Ala Tyr Glu Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Gln Ile       Thr Leu                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Gln Ala Gly Ile - # Ala Glu Arg Asp Asp Arg       Ala Tyr                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Leu Glu Gly Ala Cys Val Gln Ser - # Leu Arg Arg Tyr Leu Gln        Leu Arg                                                                                           - #   165              - #   170              - #         175                                                                              - -      Lys Glu Thr Leu Leu Cys Thr Asp - # Pro Pro Lys Ala His Val       Thr His                                                                                          180 - #                185 - #                190            - -      His Pro Arg Ser Tyr Gly Ala Val - # Thr Leu Arg Cys Trp Ala        Leu Gly                                                                                      195     - #            200     - #            205                 - -      Phe Tyr Pro Ala Asp Ile Thr Leu - # Thr Trp Gln Leu Asn Gly       Glu Glu                                                                                  210         - #        215         - #        220                     - -      Leu Thr Gln Asp Met Glu Leu Val - # Glu Thr Arg Pro Ala Gly       Asp Gly                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Thr Phe Gln Lys Trp Ala Ser Val - # Val Val Pro Leu Gly Lys        Glu Gln                                                                                           - #   245              - #   250              - #         255                                                                              - -      Asn Tyr Thr Cys His Val Asn His - # Glu Gly Leu Pro Glu Pro       Leu Thr                                                                                          260 - #                265 - #                270            - -      Leu Arg Trp Glu Pro Pro Pro Ser - # Thr Val Ser Asn Met Ala        Asn Val                                                                                      275     - #            280     - #            285                 - -      Ala Ile Leu Val Val Leu Val Ala - # Trp Pro Ser Leu Glu Leu       Trp Trp                                                                                  290         - #        295         - #        300                     - -      Ile Leu                                                                  305                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:76:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 182 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                              - -      Gly Gln His Ser Leu Gln Tyr Phe - # His Thr Ala Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Trp Phe Ile Ser - # Val Gly Tyr Val Asp Gln       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Ile Ala Lys Gly His Glu Gln - # Ser Phe Arg Gly Ser Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala Gln Ser Tyr Tyr Asn Gln Ser - # Lys Gly Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Asp Met Gly - # Ser Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Leu Gln Phe Ala Tyr Glu Gly - # Arg Asp Tyr Ile Ala Leu        Asn Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Val - # Asp Met Ala Ala Gln Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ile - # Ala Glu Lys Asp Gln Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Met Glu Ser Leu - # Arg Arg Tyr Leu Gln Leu        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Leu Arg Thr                                                              180                                                           - -  - - (2) INFORMATION FOR SEQ ID NO:77:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 301 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                              - -      Gly Ser His Ser Met Arg Tyr Phe - # Glu Thr Ser Val Ser Arg       Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Arg Phe Ile Ile - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Thr Pro Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Met Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Gln Arg Ala Lys Gly Asn Glu Gln - # Ser Phe His Val Ser Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Leu Gly His Tyr Asn Gln Ser - # Glu Ser Gly Ser His Thr        Ile Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Lys Val Gly - # Ser Asp Gly Arg Phe Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Leu Gln Tyr Ala Tyr Asp Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Val Ala Ala Ile Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Arg Lys Trp Glu Gln Ala Gly Ala - # Ala Glu Tyr Tyr Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Ala Glu Cys Val Glu Trp Leu - # Leu Arg Tyr Leu Glu Leu        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Leu Arg Thr Asp Pro - # Pro Lys Thr His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Gly Ser Glu Gly Asp Val Thr - # Leu Arg Cys Trp Pro Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Gln Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ser Val Val - # Val Pro Leu Gly Lys Glu        Gln Asn                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Asp Ser Ile Met Ser His        Ile Ala                                                                                      275     - #            280     - #            285                 - -      Asp Leu Leu Trp Pro Ser Leu Lys - # Leu Trp Trp Tyr Leu                     290         - #        295         - #        300                     - -  - - (2) INFORMATION FOR SEQ ID NO:78:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 308 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                              - -      Ser Pro His Ser Leu Arg Tyr Phe - # Thr Thr Ala Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Gly Glu Pro Arg Phe Ile Ile - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Glu Asn Pro Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Arg Trp Ile Glu Gln Glu Gly - # Pro Glu Tyr Trp Glu Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Trp Lys Ala Arg Asp Met Gly Arg - # Asn Phe Arg Val Asn Leu       Arg Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Leu Gly Tyr Tyr Asn Gln Ser - # Asn Asp Glu Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Trp Met Tyr Gly Cys Asp Val Gly - # Pro Asp Gly Arg Leu Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr Cys Gln Glu Ala Tyr Asp Gly - # Gln Asp Tyr Ile Ser Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Arg Ser Trp Thr Ala Asn - # Asp Ile Ala Ser Gln Ile       Ser Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Ser Glu Ala Val Asp Glu - # Ala His Gln Gln Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Gln Gly Pro Cys Val Glu Trp Leu - # His Arg Tyr Leu Arg Leu        Gly Asn                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Gln Arg Ser Asp Pro - # Pro Lys Ala His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Ser Glu Asp Glu Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Met Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Leu Gly Lys Glu        Gln Tyr                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Pro Ser Thr - # Val Ser Asn Met Val Ile        Ile Ala                                                                                      275     - #            280     - #            285                 - -      Val Leu Val Val Leu Gly Ala Val - # Ile Ile Leu Gly Ala Val       Val Ala                                                                                  290         - #        295         - #        300                     - -      Phe Val Met Lys                                                          305                                                                       - -  - - (2) INFORMATION FOR SEQ ID NO:79:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 289 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                              - -      Gly Ser His Ser Leu Arg Tyr Phe - # Tyr Thr Ala Leu Ser Arg       Pro Ala                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ile Ser Glu Pro Trp Tyr Ile Ala - # Val Gly Tyr Leu Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Ala Arg Phe Asp Ser Ala Gly - # Glu Thr Gly Thr Tyr Lys        Leu Ser                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Val Glu Gln Glu Gly - # Pro Glu Tyr Trp Ala Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Glu Ile Val Thr Ser Asn Ala Gln - # Phe Phe Arg Glu Asn Leu       Gln Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Met Leu Asp Tyr Tyr Asn Leu Ser - # Gln Asn Gly Ser His Thr        Ile Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Val Met Tyr Gly Cys Glu Val Glu - # Phe Phe Gly Ser Leu Phe       Arg Ala                                                                                          100 - #                105 - #                110            - -      Tyr Glu Gln His Gly Tyr Asp Gly - # Gln Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Met Ala Ala Glu Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Ser Lys Trp Glu Gln Ala Gly Tyr - # Thr Glu Leu Arg Arg Thr       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Pro Cys Lys Asp Ser Leu - # Leu Arg Tyr Leu Glu Asn        Arg Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Lys Thr Gln Glu Cys Thr Asp Pro - # Pro Lys Thr His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Ala Arg Pro Glu Gly Asp Val Thr - # Leu Arg Cys Trp Ala Leu        Gly Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala His Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Ile Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Ser Gly Glu Glu        Gln Lys                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Pro Pro Ser Ser Met - # Pro Asn Arg Thr Thr Val        Arg Ala                                                                                      275     - #            280     - #            285                 - -      Leu                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:80:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 290 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                              - -      Gly Ser His Ser Leu Arg Tyr Phe - # Tyr Thr Ala Leu Ser Arg       Pro Ala                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ile Ser Glu Pro Trp Tyr Ile Ala - # Val Gly Tyr Leu Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asn Ser Ser Gly - # Glu Thr Ala Thr Tyr Lys        Leu Ser                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Val Glu Gln Glu Gly - # Pro Glu Tyr Trp Ala Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Glu Ile Val Thr Ser Asn Ala Gln - # Phe Phe Arg Glu Asn Leu       Gln Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Met Leu Asp Tyr Tyr Asn Leu Ser - # Gln Asn Gly Ser His Thr        Ile Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Val Met Tyr Gly Cys Glu Val Glu - # Phe Phe Gly Ser Leu Phe       Arg Ala                                                                                          100 - #                105 - #                110            - -      Tyr Glu Gln His Gly Tyr Asp Gly - # Arg Asp Tyr Ile Ala Leu        Met Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Lys Thr Trp Thr Ala Ala - # Asp Thr Ala Ala Glu Ile       Thr Arg                                                                                  130         - #        135         - #        140                     - -      Ser Lys Trp Glu Gln Ala Gly Tyr - # Thr Glu Leu Arg Arg Thr       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Pro Cys Lys Asp Ser Leu - # Arg Leu Tyr Leu Glu Asn        Arg Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Lys Thr Gln Glu Cys Thr Asp Pro - # Pro Lys Thr His Val Thr       His His                                                                                          180 - #                185 - #                190            - -      Pro Arg Pro Glu Gly Tyr Val Thr - # Leu Arg Cys Trp Ala Leu        Arg Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Asp Ile Thr Leu Thr - # Trp Gln Leu Asn Gly Glu       Glu Leu                                                                                  210         - #        215         - #        220                     - -      Ile Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Leu Gly Lys Glu        Gln Lys                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Tyr His Glu - # Gly Leu Pro Glu Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Arg Trp Glu Leu Pro Gln Thr Ser - # Met Pro Asn Arg Thr Thr        Val Arg                                                                                      275     - #            280     - #            285                 - -      Ala Leu                                                                      290                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:81:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 104 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                              - -      Gly Ser His Ser Leu Lys Tyr Phe - # Tyr Thr Ala Leu Ser Arg       Pro Ala                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ile Ser Glu Pro Trp Tyr Ile Ala - # Gly Gly Tyr Leu Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Arg Cys Phe Glu Ser Ala Gly - # Glu Ser Ala Thr Tyr Lys        Leu Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Val Glu Gln Glu Gly - # Pro Glu Tyr Trp Ala Arg       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Glu Ile Val Thr Ser Asn Ala Gln - # Phe Phe Arg Val Glu Asn       Leu Gln                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Thr Met Leu Asp Tyr Tyr Ser Leu - # Ser Gln Asn Gly Ser His        Thr Ile                                                                                           - #   85               - #   90               - #         95                                                                               - -      Gln Val Met Tyr Gly Cys Glu Val                                                      100                                                           - -  - - (2) INFORMATION FOR SEQ ID NO:82:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 108 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                              - -      Asp Pro Pro Lys Thr His Val Thr - # His His Pro Arg Pro Glu       Gly Tyr                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Val Thr Leu Arg Cys Trp Ala Leu - # Arg Phe Tyr Pro Ala Asp       Ile Thr                                                                                          20 - #                 25 - #                 30             - -      Leu Thr Trp Gln Leu Asn Gly Glu - # Glu Leu Ile Gln Asp Thr        Glu Leu                                                                                      35     - #             40     - #             45                  - -      Val Glu Thr Arg Pro Ala Gly Asp - # Gly Thr Phe Gln Lys Trp       Ala Ala                                                                                  50         - #         55         - #         60                      - -      Val Val Val Pro Leu Gly Lys Glu - # Gln Lys Tyr Thr Cys His       Val Tyr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      His Glu Gly Leu Pro Glu Pro Leu - # Thr Leu Arg Trp Glu Leu        Pro Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Thr Ser Met Pro Asn Arg Thr Thr - # Val Arg Ala Leu                                  100 - #                105                                    - -  - - (2) INFORMATION FOR SEQ ID NO:83:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 184 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                              - -      Gly Ser Leu Phe Arg Ala Tyr Glu - # Gln His Gly Tyr Asp Gly       Arg Asp                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Tyr Ile Ala Leu Met Glu Asp Val - # Lys Thr Trp Thr Ala Ala       Asp Met                                                                                          20 - #                 25 - #                 30             - -      Ala Ala Glu Ile Thr Arg Ser Lys - # Trp Glu Gln Ala Gly Tyr        Thr Glu                                                                                      35     - #             40     - #             45                  - -      Leu Arg Arg Thr Tyr Leu Glu Gly - # Pro Cys Lys Asp Ser Leu       Leu Arg                                                                                  50         - #         55         - #         60                      - -      Tyr Leu Glu Asn Arg Lys Lys Gln - # Glu Cys Thr Asp Pro Pro       Lys Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ala His Val Thr His His Pro Arg - # Pro Glu Gly Tyr Val Thr        Leu Arg                                                                                           - #   85               - #   90               - #         95                                                                               - -      Cys Trp Ala Leu Gly Phe Tyr Pro - # Ala Asp Ile Thr Leu Thr       Trp Gln                                                                                          100 - #                105 - #                110            - -      Leu Asn Gly Glu Glu Leu Ile Gln - # Asp Met Glu Leu Val Glu        Thr Arg                                                                                      115     - #            120     - #            125                 - -      Pro Ala Gly Asp Gly Thr Phe Gln - # Lys Trp Ala Ala Val Val       Val Pro                                                                                  130         - #        135         - #        140                     - -      Ser Gly Glu Glu Gln Lys Tyr Thr - # Cys His Val Tyr His Glu       Gly Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Pro Glu Pro Leu Thr Leu Arg Trp - # Glu Pro Pro Gln Ser Ser        Met Pro                                                                                           - #   165              - #   170              - #         175                                                                              - -      Thr Arg Thr Ile Val Arg Ala Leu                                                      180                                                           - -  - - (2) INFORMATION FOR SEQ ID NO:84:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 92 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                              - -      Val Thr Leu Arg Cys Trp Ala Leu - # Gly Phe Tyr Pro Ala Asp       Ile Thr                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Leu Thr Trp Gln Leu Asn Gly Glu - # Glu Leu Ile Gln Asp Thr       Glu Leu                                                                                          20 - #                 25 - #                 30             - -      Val Glu Thr Arg Pro Ala Gly Asp - # Gly Thr Phe Gln Lys Trp        Ala Ala                                                                                      35     - #             40     - #             45                  - -      Leu Val Val Pro Ser Gly Glu Glu - # Gln Lys Tyr Thr Cys His       Val Tyr                                                                                  50         - #         55         - #         60                      - -      His Lys Gly Leu Pro Glu Pro Leu - # Thr Leu Arg Trp Glu Pro       Pro Gln                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Ser Ser Met Pro Asn Arg Thr Thr - # Val Arg Ala Leu                                   - #   85               - #   90                              - -  - - (2) INFORMATION FOR SEQ ID NO:85:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 38 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 14..15                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                              - -      Asn Thr Gly Gly Lys Gly Val Asn - # Tyr Ala Leu Ala Pro Xaa        Xaa Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ser Gln Thr Ser Asp Leu Ser Leu - # Pro Asp Gly Lys Val Met       Val His                                                                                          20 - #                 25 - #                 30             - -      Asp Pro His Ser Leu Ala                                                          35                                                                - -  - - (2) INFORMATION FOR SEQ ID NO:86:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 42 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 18..19                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                              - -      Met Arg Arg Arg Asn Thr Gly Gly - # Lys Gly Gly Asp Tyr Ala        Leu Ala                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Pro Xaa Xaa Gly Ser Gln Thr Ser - # Asp Leu Ser Leu Pro Asp       Cys Lys                                                                                          20 - #                 25 - #                 30             - -      Val Met Val His Asp Pro His Ser - # Leu Ala                                      35     - #             40                                         - -  - - (2) INFORMATION FOR SEQ ID NO:87:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 32 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 17..18                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                              - -      Arg Arg Arg Asn Thr Gly Gly Lys - # Gly Gly Asp Tyr Ala Leu        Ala Pro                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Xaa Xaa Gly Ser Gln Ser Ser Asp - # Met Ser Leu Pro Asp Cys       Lys Val                                                                                          20 - #                 25 - #                 30             - -  - - (2) INFORMATION FOR SEQ ID NO:88:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 29 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 14..15                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                              - -      Asn Thr Gly Gly Lys Gly Gly Asp - # Tyr Thr Leu Ala Pro Xaa        Xaa Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Ser Gln Ser Ser Glu Met Ser Leu - # Arg Asp Cys Lys Ala                             20 - #                 25                                     - -  - - (2) INFORMATION FOR SEQ ID NO:89:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 32 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 17..18                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                              - -      Arg Arg Arg Asn Thr Gly Gly Lys - # Gly Gly Asp Tyr Ala Leu        Ala Pro                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Xaa Xaa Gly Ser Gln Ser Ser Glu - # Met Ser Leu Arg Asp Cys       Lys Ala                                                                                          20 - #                 25 - #                 30             - -  - - (2) INFORMATION FOR SEQ ID NO:90:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                              - -      Arg Arg Arg His Ile Gly Val Lys - # Gly Cys                              1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:91:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 6..7                                                            (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                              - -      Tyr Ala His Val Leu Xaa Xaa Gly - # Ser Lys Ser Phe Gln Thr        Ser Asp                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Trp Pro Gln Lys Ala                                                                  20                                                            - -  - - (2) INFORMATION FOR SEQ ID NO:92:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 47 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 34..35                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                              - -      Leu Gly Ala Met Ile Ile Leu Gly - # Phe Met Ser Gly Ser Val        Met Met                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Trp Met Arg Lys Asn Asn Gly Gly - # Asn Gly Asp Asp Asn Thr       Ala Ala                                                                                          20 - #                 25 - #                 30             - -      Tyr Xaa Xaa Gln Met Glu Arg Glu - # His Leu Ser Leu Trp Ser        Gln                                                                                          35     - #             40     - #             45                  - -  - - (2) INFORMATION FOR SEQ ID NO:93:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 70 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 34..35                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                              - -      Leu Gly Ala Met Ile Ile Leu Gly - # Phe Met Ser Gly Ser Val        Met Met                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Trp Met Arg Lys Asn Asn Gly Gly - # Asn Gly Asp Asp Asn Thr       Ala Ala                                                                                          20 - #                 25 - #                 30             - -      Tyr Xaa Xaa Gln Asn Glu Arg Glu - # His Leu Ser Leu Thr Pro        Arg Ala                                                                                      35     - #             40     - #             45                  - -      Glu Ser Glu Ala Leu Gly Val Glu - # Ala Gly Met Lys Asp Leu       Pro Ser                                                                                  50         - #         55         - #         60                      - -      Ala Pro Pro Leu Val Ser                                                  65             - #     70                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:94:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 70 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 34..35                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                              - -      Leu Gly Ala Met Ile Ile Leu Gly - # Phe Met Ser Gly Gly Val        Met Met                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Trp Met Arg Lys Asn Asn Gly Gly - # Asn Gly Asp Asp Asn Thr       Ala Ala                                                                                          20 - #                 25 - #                 30             - -      Cys Xaa Xaa Gln Met Glu Arg Glu - # His Leu Ser Leu Ser Pro        Arg Ala                                                                                      35     - #             40     - #             45                  - -      Glu Ser Glu Ala Leu Gly Val Glu - # Ala Gly Met Lys Asp Leu       Pro Ser                                                                                  50         - #         55         - #         60                      - -      Ala Pro Pro Leu Val Ser                                                  65             - #     70                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:95:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 64 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 34..35                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                              - -      Leu Gly Ala Met Ile Ile Leu Gly - # Ile Met Ser Gly Ser Val        Met Met                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Trp Met Arg Lys Asn Lys Gly Gly - # Asn Gly Gln Asp Asn Thr       Ala Ala                                                                                          20 - #                 25 - #                 30             - -      Cys Xaa Xaa Gln Met Glu Arg Glu - # His Leu Ser Leu Ser Pro        Arg Ala                                                                                      35     - #             40     - #             45                  - -      Glu Ser Glu Ala Leu Gly Val Glu - # Ala Gly Leu Lys Asp Leu       Pro Ser                                                                                  50         - #         55         - #         60                      - -  - - (2) INFORMATION FOR SEQ ID NO:96:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 70 amino - #acids                                                 (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 34..35                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                              - -      Leu Gly Ala Met Val Ile Leu Gly - # Val Met Arg Gly Ser Gly        Met Met                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Trp Met Arg Lys Asn Lys Gly Gly - # Asn Arg Asp Asp Asn Thr       Ala Ala                                                                                          20 - #                 25 - #                 30             - -      Cys Xaa Xaa Gln Met Glu Arg Glu - # His Leu Ser Leu Ser Ala        Gly Asp                                                                                      35     - #             40     - #             45                  - -      Glu Ser Asp Ala Leu Gly Val Glu - # Ala Gly Leu Lys Glu Leu       Pro Thr                                                                                  50         - #         55         - #         60                      - -      Ala Pro Pro Leu Val Pro                                                  65             - #     70                                                 - -  - - (2) INFORMATION FOR SEQ ID NO:97:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                              - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser       Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #               5                  - -      Phe Thr Ser Val Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Gln Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Gly Glu Thr - # Arg Lys Val Lys Ala His       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr His Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Val Gln - # Arg Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Ser Asp Trp Arg Phe Leu Arg Gly - # Tyr His Gln Tyr Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Ala Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Leu Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Ala Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:98:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                              - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                           - #-5                  - # 1               5                 - -      Tyr Thr Ser Val Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                   10        - #          15        - #          20                     - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Gln Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Gly Glu Thr - # Arg Lys Val Lys Ala His       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr His Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Val Gln - # Arg Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Ser Asp Trp Arg Phe Leu Arg Gly - # Tyr His Gln Tyr Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Ala Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Leu Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Ala Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:99:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                              - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #              5                   - -      Phe Thr Ser Val Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Gln Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Gly Glu Thr - # Arg Lys Val Lys Ala His       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr His Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Val Gln - # Arg Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Ser Asp Gly Arg Phe Leu Arg Gly - # Tyr His Gln Tyr Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Thr Ala       His Glu                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Trp Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #         175        - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Ala Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:100:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                             - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #              5                   - -      Tyr Thr Ser Val Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Gln Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Gly Glu Thr - # Arg Lys Val Lys Ala His       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr His Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Val Gln - # Arg Met Phe Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Ser Asp Gly Arg Phe Leu Arg Gly - # Tyr His Gln Tyr Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Ala Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Leu Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Ala Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:101:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                             - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #              5                   - -      Tyr Thr Ser Val Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Arg Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Gly Glu Thr - # Arg Lys Val Lys Ala His       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr His Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Leu Val Gln - # Arg Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Phe Asp Trp Arg Phe Leu Arg Gly - # Tyr His Gln Tyr Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Thr Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Leu Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Ala Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:102:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                             - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #              5                   - -      Tyr Thr Ser Met Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Arg Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Arg Asn Thr - # Arg Asn Val Lys Ala Gln       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr Asp Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Ile Gln - # Arg Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Phe Asp Gly Arg Phe Leu Arg Gly - # Tyr Arg Gln Asp Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Ala Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Trp Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Val Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:103:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                             - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #              5                   - -      Tyr Thr Ser Met Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Gln Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Arg Asn Thr - # Arg Asn Val Lys Ala Gln       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr Asp Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Ile Gln - # Arg Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Phe Asp Gly Arg Phe Leu Arg Gly - # Tyr Arg Gln Asp Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Ala Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Trp Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Val Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #                305 - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:104:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 365 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                             - -      Met Ala Val Met Ala Pro Arg Thr - # Leu Val Leu Leu Leu Ser        Gly Ala                                                                              -24             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Ala Leu Thr Gln Thr Trp Ala - # Gly Ser His Ser Met Arg       Tyr Phe                                                                                          -5 - #                 1 - #              5                   - -      Tyr Thr Ser Val Ser Arg Pro Gly - # Arg Gly Glu Pro Arg Phe       Ile Ala                                                                                  10         - #         15         - #         20                      - -      Val Gly Tyr Val Asp Asp Thr Gln - # Phe Val Arg Phe Asp Ser       Asp Ala                                                                              25             - #     30             - #     35             - #         40                                                                            - -      Ala Ser Gln Arg Met Glu Pro Arg - # Ala Pro Trp Ile Glu Gln        Glu Gly                                                                                           - #   45               - #   50               - #         55                                                                               - -      Pro Glu Tyr Trp Asp Phe Asn Thr - # Arg Asn Val Lys Ala Gln       Ser Gln                                                                                          60 - #                 65 - #                 70             - -      Thr Asp Arg Val Asp Leu Ser Thr - # Leu Arg Gly Tyr Tyr Asn        Gln Ser                                                                                      75     - #             80     - #             85                  - -      Glu Ala Gly Ser His Thr Ile Gln - # Met Met Tyr Gly Cys Asp       Val Gly                                                                                  90         - #         95         - #         100                     - -      Ser Asp Gly Arg Phe Leu Arg Gly - # Tyr Arg Gln Asp Ala Tyr       Asp Gly                                                                              105             - #    110             - #    115             - #        120                                                                           - -      Lys Asp Tyr Ile Ala Leu Lys Glu - # Asp Leu Arg Ser Trp Thr        Ala Ala                                                                                           - #   125              - #   130              - #         135                                                                              - -      Asp Met Ala Ala Gln Thr Thr Lys - # His Lys Trp Glu Ala Ala       His Val                                                                                          140 - #                145 - #                150            - -      Ala Glu Gln Trp Arg Ala Tyr Leu - # Glu Gly Thr Cys Val Glu        Trp Leu                                                                                      155     - #            160     - #            165                 - -      Arg Arg Tyr Leu Glu Asn Gly Lys - # Glu Thr Leu Gln Arg Thr       Asp Ala                                                                                  170         - #        175         - #        180                     - -      Pro Lys Thr His Met Thr His His - # Ala Val Ser Asp His Glu       Ala Thr                                                                              185             - #    190             - #    195             - #        200                                                                           - -      Leu Arg Cys Trp Ala Leu Ser Phe - # Tyr Pro Ala Glu Ile Thr        Leu Thr                                                                                           - #   205              - #   210              - #         215                                                                              - -      Trp Gln Arg Asp Gly Glu Asp Gln - # Thr Gln Asp Thr Glu Leu       Val Glu                                                                                          220 - #                225 - #                230            - -      Thr Arg Pro Ala Gly Asp Gly Thr - # Phe Gln Lys Trp Val Ala        Val Val                                                                                      235     - #            240     - #            245                 - -      Val Pro Ser Gly Gln Glu Gln Arg - # Tyr Thr Cys His Val Gln       His Glu                                                                                  250         - #        255         - #        260                     - -      Gly Leu Pro Lys Pro Leu Thr Leu - # Pro Trp Glu Pro Ser Ser       Gln Pro                                                                              265             - #    270             - #    275             - #        280                                                                           - -      Thr Ile Pro Ile Val Gly Ile Ile - # Ala Gly Leu Val Leu Phe        Gly Ala                                                                                           - #   285              - #   290              - #         295                                                                              - -      Val Ile Thr Gly Ala Val Val Ala - # Ala Val Met Trp Arg Arg       Lys Ser                                                                                          300 - #               305  - #                310            - -      Ser Asp Arg Lys Gly Gly Ser Tyr - # Ser Gln Ala Ala Ser Ser        Asp Ser                                                                                      315     - #            320     - #            325                 - -      Ala Gln Gly Ser Asp Val Ser Leu - # Thr Ala Cys Lys Val                     330         - #        335         - #        340                     - -  - - (2) INFORMATION FOR SEQ ID NO:105:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 274 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                             - -      Gly Ser His Ser Met Arg Tyr Phe - # Phe Thr Ser Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Arg Gly Glu Pro Arg Phe Ile Ala - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Ala Ser Gln Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Ile Glu Gln Glu Gly - # Pro Glu Tyr Trp Asp Gly       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Arg Lys Val Lys Ala His Ser Gln - # Thr His Arg Val Asp Leu       Ser Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Arg Gly Tyr Tyr Asn Gln Ser - # Glu Ala Gly Ser His Thr        Val Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Met Cys Gly Cys Asp Val Gly - # Ser Asp Trp Arg Phe Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr His Gln Tyr Ala Tyr Asp Gly - # Lys Asp Tyr Ile Ala Leu        Lys Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Arg Ser Trp Thr Ala Ala - # Asp Met Ala Ala Gln Thr       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Ala Ala His Val - # Ala Glu Gln Leu Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Glu Asn        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Gln Arg Thr Asp Ala - # Pro Lys Thr His Met Thr       His His                                                                                          180 - #                185 - #                190            - -      Ala Val Ser Asp His Glu Ala Thr - # Leu Arg Cys Trp Ala Leu        Ser Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Glu Ile Thr Leu Thr - # Trp Gln Arg Asp Gly Glu       Asp Gln                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Ser Gly Gln Glu        Gln Arg                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Gln His Glu - # Gly Leu Pro Lys Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Pro Trp                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:106:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 274 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                             - -      Gly Ser His Ser Met Arg Tyr Phe - # Phe Thr Ser Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Arg Gly Glu Pro Arg Phe Ile Ala - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Ala Ser Gln Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Ile Glu Gln Glu Gly - # Pro Glu Tyr Trp Asp Gly       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Arg Lys Val Lys Ala His Ser Gln - # Thr His Arg Val Asp Leu       Ser Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Arg Gly Tyr Tyr Asn Gln Ser - # Glu Ala Gly Ser His Thr        Val Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Met Tyr Gly Cys Asp Val Gly - # Ser Asp Trp Arg Phe Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr His Gln Tyr Ala Tyr Asp Gly - # Lys Asp Tyr Ile Ala Leu        Lys Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Arg Ser Trp Thr Ala Ala - # Asp Met Ala Ala Gln Thr       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Ala Ala His Val - # Ala Glu Gln Leu Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Glu Asn        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Gln Arg Thr Asp Ala - # Pro Lys Thr His Met Thr       His His                                                                                          180 - #                185 - #                190            - -      Ala Val Ser Asp His Glu Ala Thr - # Leu Arg Cys Trp Ala Leu        Ser Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Glu Ile Thr Leu Thr - # Trp Gln Arg Asp Gly Glu       Asp Gln                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Glu Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Ser Gly Gln Glu        Gln Arg                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Gln His Glu - # Gly Leu Pro Lys Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Pro Trp                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:107:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 274 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                             - -      Gly Ser His Ser Met Arg Tyr Phe - # Phe Thr Ser Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Arg Gly Glu Pro Arg Phe Ile Ala - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Ala Ser Arg Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Ile Glu Gln Glu Gly - # Pro Glu Tyr Trp Asp Gly       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Arg Lys Val Lys Ala His Ser Gln - # Thr His Arg Val Asp Leu       Ser Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Arg Gly Tyr Tyr Asn Gln Ser - # Glu Ala Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Met Tyr Gly Cys Asp Val Gly - # Ser Asp Trp Arg Phe Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr His Gln Tyr Ala Tyr Asp Gly - # Lys Asp Tyr Ile Ala Leu        Lys Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Arg Ser Trp Thr Ala Ala - # Asp Met Ala Ala Gln Thr       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Ala Ala His Val - # Ala Glu Gln Trp Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Glu Asn        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Gln Arg Thr Asp Ala - # Pro Lys Thr His Met Thr       His His                                                                                          180 - #                185 - #                190            - -      Ala Val Ser Asp His Glu Ala Thr - # Leu Arg Cys Trp Ala Leu        Ser Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Glu Ile Thr Leu Thr - # Trp Gln Arg Asp Gly Glu       Asp Gln                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Ser Gly Gln Glu        Gln Arg                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Gln His Glu - # Gly Leu Pro Lys Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Pro Trp                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:108:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 274 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                             - -      Gly Ser His Ser Met Arg Tyr Phe - # Tyr Thr Ser Val Ser Arg        Pro Gly                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Arg Gly Glu Pro Arg Phe Ile Ala - # Val Gly Tyr Val Asp Asp       Thr Gln                                                                                          20 - #                 25 - #                 30             - -      Phe Val Arg Phe Asp Ser Asp Ala - # Ala Ser Arg Arg Met Glu        Pro Arg                                                                                      35     - #             40     - #             45                  - -      Ala Pro Trp Ile Glu Gln Glu Gly - # Pro Glu Tyr Trp Asp Gly       Glu Thr                                                                                  50         - #         55         - #         60                      - -      Arg Asn Val Lys Ala His Ser Gln - # Thr His Arg Val Asp Leu       Ser Thr                                                                              65             - #     70             - #     75             - #         80                                                                            - -      Leu Arg Gly Tyr Tyr Asn Gln Ser - # Glu Ala Gly Ser His Thr        Leu Gln                                                                                           - #   85               - #   90               - #         95                                                                               - -      Arg Met Tyr Gly Cys Asp Val Gly - # Ser Asp Trp Arg Phe Leu       Arg Gly                                                                                          100 - #                105 - #                110            - -      Tyr His Gln Tyr Ala Tyr Asp Gly - # Lys Asp Tyr Ile Ala Leu        Lys Glu                                                                                      115     - #            120     - #            125                 - -      Asp Leu Arg Ser Trp Thr Ala Ala - # Asp Met Ala Ala Gln Thr       Thr Lys                                                                                  130         - #        135         - #        140                     - -      His Lys Trp Glu Ala Ala His Val - # Ala Glu Gln Trp Arg Ala       Tyr Leu                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Glu Gly Thr Cys Val Glu Trp Leu - # Arg Arg Tyr Leu Glu Asn        Gly Lys                                                                                           - #   165              - #   170              - #         175                                                                              - -      Glu Thr Leu Gln Arg Thr Asp Ala - # Pro Lys Thr His Met Thr       His His                                                                                          180 - #                185 - #                190            - -      Ala Val Ser Asp His Glu Ala Thr - # Leu Arg Cys Trp Ala Leu        Ser Phe                                                                                      195     - #            200     - #            205                 - -      Tyr Pro Ala Glu Ile Thr Leu Thr - # Trp Gln Arg Asp Gly Glu       Asp Gln                                                                                  210         - #        215         - #        220                     - -      Thr Gln Asp Thr Glu Leu Val Glu - # Thr Arg Pro Ala Gly Asp       Gly Thr                                                                              225             - #    230             - #    235             - #        240                                                                           - -      Phe Gln Lys Trp Ala Ala Val Val - # Val Pro Ser Gly Gln Glu        Gln Arg                                                                                           - #   245              - #   250              - #         255                                                                              - -      Tyr Thr Cys His Val Gln His Glu - # Gly Leu Pro Lys Pro Leu       Thr Leu                                                                                          260 - #                265 - #                270            - -      Pro Trp                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:109:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 253 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 7                                                               (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                             - -      Met Ala Ile Ser Gly Val Pro Val - # Leu Gly Phe Phe Ile Ile        Ala Val                                                                              -25             - #    -20             - #    -15             - #        -10                                                                           - -      Leu Met Ser Ala Gln Glu Ser Trp - # Ala Ile Lys Glu Glu His        Val Xaa                                                                                           - #   -5               - #   1               - #5           - -      Ile Ile Gln Ala Glu Phe Tyr Leu - # Asn Pro Asp Gln Ser Gly        Glu Phe                                                                                      10     - #             15     - #             20                  - -      Met Phe Asp Phe Asp Gly Asp Glu - # Ile Phe His Val Asp Met       Ala Lys                                                                                  25         - #         30         - #         35                      - -      Lys Glu Thr Val Trp Arg Leu Glu - # Glu Phe Gly Arg Phe Ala       Ser Phe                                                                              40             - #     45             - #     50             - #         55                                                                            - -      Glu Ala Gln Gly Ala Leu Ala Asn - # Ile Ala Val Asp Lys Ala        Asn Leu                                                                                           - #   60               - #   65               - #         70                                                                               - -      Glu Ile Met Thr Lys Arg Ser Asn - # Tyr Thr Pro Ile Thr Asn       Val Pro                                                                                          75 - #                 80 - #                 85             - -      Pro Glu Val Thr Val Leu Thr Asn - # Ser Pro Val Glu Leu Arg        Glu Pro                                                                                      90     - #             95     - #             100                 - -      Asn Val Leu Ile Cys Phe Ile Asp - # Lys Phe Thr Pro Pro Val       Val Asn                                                                                  105         - #        110         - #        115                     - -      Val Thr Trp Leu Arg Asn Gly Lys - # Pro Val Thr Thr Gly Val       Ser Glu                                                                              120             - #    125             - #    130             - #        135                                                                           - -      Thr Val Phe Leu Pro Arg Glu Asp - # His Leu Phe Arg Lys Phe        His Tyr                                                                                           - #   140              - #   145              - #         150                                                                              - -      Leu Pro Phe Leu Pro Ser Thr Glu - # Asp Val Tyr Asp Cys Arg       Val Glu                                                                                          155 - #                160 - #                165            - -      His Trp Gly Leu Asp Glu Pro Leu - # Leu Lys His Trp Glu Phe        Asp Ala                                                                                      170     - #            175     - #            180                 - -      Pro Ser Pro Leu Pro Glu Thr Thr - # Glu Asn Val Val Cys Ala       Leu Thr                                                                                  185         - #        190         - #        195                     - -      Val Gly Leu Val Gly Ile Ile Ile - # Gly Thr Ile Phe Ile Ile       Lys Gly                                                                              200             - #    205             - #    210             - #        215                                                                           - -      Leu Arg Lys Ser Asn Ala Ala Glu - # Arg Arg Gly Pro Leu                               - #   220              - #   225                             - -  - - (2) INFORMATION FOR SEQ ID NO:110:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 255 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                             - -      Met Ile Leu Asn Lys Ala Leu Leu - # Leu Gly Ala Leu Ala Leu        Thr Thr                                                                              -25             - #    -20             - #    -15             - #        -10                                                                           - -      Val Met Ser Pro Cys Gly Gly Glu - # Asp Ile Val Ala Asp His        Val Ala                                                                                           - #   -5               - #   1               - #5           - -      Ser Cys Gly Val Asn Leu Tyr Gln - # Phe Tyr Gly Pro Ser Gly        Gln Tyr                                                                                      10     - #             15     - #             20                  - -      Thr His Glu Phe Asp Gly Asp Glu - # Gln Phe Tyr Val Asp Leu       Glu Arg                                                                                  25         - #         30         - #         35                      - -      Lys Glu Thr Ala Trp Arg Trp Pro - # Glu Phe Ser Lys Phe Gly       Gly Phe                                                                              40             - #     45             - #     50             - #         55                                                                            - -      Asp Pro Gln Gly Ala Leu Arg Asn - # Met Ala Val Ala Lys His        Asn Leu                                                                                           - #   60               - #   65               - #         70                                                                               - -      Asn Ile Met Ile Lys Arg Tyr Asn - # Ser Thr Ala Ala Thr Asn       Glu Val                                                                                          75 - #                 80 - #                 85             - -      Pro Glu Val Thr Val Phe Ser Lys - # Ser Pro Val Thr Leu Gly        Gln Pro                                                                                      90     - #             95     - #             100                 - -      Asn Thr Leu Ile Cys Leu Val Asp - # Asn Ile Phe Pro Pro Val       Val Asn                                                                                  105         - #        110         - #        115                     - -      Ile Thr Trp Leu Ser Asn Gly Gln - # Ser Val Thr Glu Asp Val       Ser Glu                                                                              120             - #    125             - #    130             - #        135                                                                           - -      Thr Ser Phe Leu Ser Lys Ser Asp - # His Ser Phe Phe Lys Ile        Ser Tyr                                                                                           - #   140              - #   145              - #         150                                                                              - -      Leu Thr Phe Leu Pro Ser Ala Asp - # Glu Ile Tyr Asp Cys Lys       Val Glu                                                                                          155 - #                160 - #                165            - -      His Trp Gly Leu Asp Gln Pro Leu - # Leu Lys His Trp Glu Pro        Glu Ile                                                                                      170     - #            175     - #            180                 - -      Pro Ala Pro Met Ser Glu Leu Thr - # Glu Thr Val Val Cys Ala       Leu Gly                                                                                  185         - #        190         - #        195                     - -      Leu Ser Val Gly Leu Met Gly Ile - # Val Val Gly Thr Val Phe       Ile Ile                                                                              200             - #    205             - #    210             - #        215                                                                           - -      Gln Gly Leu Arg Ser Val Gly Ala - # Ser Arg His Gln Gly Pro        Leu                                                                                               - #   220              - #   225              - #         230                                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:111:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 261 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 7                                                               (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                             - -      Met Arg Pro Glu Asp Arg Met Phe - # His Ile Arg Ala Val Ile        Leu Arg                                                                                  -30         - #        -25         - #        -20                     - -      Ala Leu Ser Leu Ala Phe Leu Leu - # Ser Leu Arg Gly Ala Gly       Ala Ile                                                                              -15             - #    -10             - #    -5              - #        1                                                                             - -      Lys Ala Asp His Val Xaa Ser Thr - # Tyr Ala Ala Phe Val Gln        Thr His                                                                                          5 - #                  - #10                  - #15          - -      Arg Pro Thr Gly Glu Phe Met Phe - # Glu Phe Asp Glu Asp Glu        Met Phe                                                                                      20     - #             25     - #             30                  - -      Tyr Val Asp Leu Asp Lys Lys Glu - # Thr Val Trp His Leu Glu       Glu Phe                                                                                  35         - #         40         - #         45                      - -      Gly Gln Ala Phe Ser Phe Glu Ala - # Gln Gly Gly Leu Ala Asn       Ile Ala                                                                              50             - #     55             - #     60             - #         65                                                                            - -      Ile Leu Asn Asn Asn Leu Asn Thr - # Leu Ile Gln Arg Ser Asn        His Thr                                                                                           - #   70               - #   75               - #         80                                                                               - -      Gln Ala Thr Asn Asp Pro Pro Glu - # Val Thr Val Phe Pro Lys       Glu Pro                                                                                          85 - #                 90 - #                 95             - -      Val Glu Leu Gly Gln Pro Asn Thr - # Leu Ile Cys His Ile Asp        Lys Phe                                                                                      100     - #            105     - #            110                 - -      Phe Pro Pro Val Leu Asn Val Thr - # Trp Leu Cys Asn Gly Glu       Leu Val                                                                                  115         - #        120         - #        125                     - -      Thr Glu Gly Val Ala Glu Ser Leu - # Phe Leu Pro Arg Thr Asp       Tyr Ser                                                                              130             - #    135             - #    140             - #        145                                                                           - -      Phe His Lys Phe His Tyr Leu Thr - # Phe Val Pro Ser Ala Glu        Asp Phe                                                                                           - #   150              - #   155              - #         160                                                                              - -      Tyr Asp Cys Arg Val Glu His Trp - # Gly Leu Asp Gln Pro Leu       Leu Lys                                                                                          165 - #                170 - #                175            - -      His Trp Glu Ala Gln Glu Pro Ile - # Gln Met Pro Glu Thr Thr        Glu Thr                                                                                      180     - #            185     - #            190                 - -      Val Leu Cys Ala Leu Gly Leu Val - # Leu Gly Leu Val Gly Phe       Ile Val                                                                                  195         - #        200         - #        205                     - -      Gly Thr Val Leu Ile Ile Lys Ser - # Leu Arg Ser Gly His Asp       Pro Arg                                                                              210             - #    215             - #    220             - #        225                                                                           - -      Ala Gln Gly Thr Leu                                                                   - #   230                                                    - -  - - (2) INFORMATION FOR SEQ ID NO:112:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 250 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                             - -      Met Ala Leu Arg Ala Gly Leu Val - # Leu Gly Phe His Thr Leu        Met Thr                                                                              -25             - #    -20             - #    -15             - #        -10                                                                           - -      Leu Leu Ser Pro Gln Glu Ala Gly - # Ala Thr Lys Ala Asp His        Met Gly                                                                                           - #   -5               - #   1               - #5           - -      Ser Tyr Gly Pro Ala Phe Tyr Gln - # Ser Tyr Gly Ala Ser Gly        Gln Phe                                                                                      10     - #             15     - #             20                  - -      Thr His Glu Phe Asp Glu Glu Gln - # Leu Phe Ser Val Asp Leu       Lys Lys                                                                                  25         - #         30         - #         35                      - -      Ser Glu Ala Val Trp Arg Leu Pro - # Glu Phe Gly Asp Phe Ala       Arg Phe                                                                              40             - #     45             - #     50             - #         55                                                                            - -      Asp Pro Gln Gly Gly Leu Ala Gly - # Ile Ala Ala Ile Lys Ala        His Leu                                                                                           - #   60               - #   65               - #         70                                                                               - -      Asp Ile Leu Val Glu Arg Ser Asn - # Arg Ser Arg Ala Ile Asn       Val Pro                                                                                          75 - #                 80 - #                 85             - -      Pro Arg Val Thr Val Leu Pro Lys - # Ser Arg Val Glu Leu Gly        Gln Pro                                                                                      90     - #             95     - #             100                 - -      Asn Ile Leu Ile Cys Ile Val Asp - # Asn Ile Phe Pro Pro Val       Ile Asn                                                                                  105         - #        110         - #        115                     - -      Ile Thr Trp Leu Arg Asn Gly Gln - # Thr Val Thr Glu Gly Val       Ala Gln                                                                              120             - #    125             - #    130             - #        135                                                                           - -      Thr Ser Phe Tyr Ser Gln Pro Asp - # His Leu Phe Arg Lys Phe        His Tyr                                                                                           - #   140              - #   145              - #         150                                                                              - -      Leu Pro Phe Val Pro Ser Ala Glu - # Asp Val Tyr Asp Cys Gln       Val Glu                                                                                          155 - #                160 - #                165            - -      His Trp Gly Leu Asp Ala Pro Leu - # Leu Arg His Trp Glu Leu        Gln Val                                                                                      170     - #            175     - #            180                 - -      Pro Ile Pro Pro Pro Asp Ala Met - # Glu Thr Leu Val Cys Ala       Leu Gly                                                                                  185         - #        190         - #        195                     - -      Leu Ala Ile Gly Leu Val Gly Phe - # Leu Val Gly Thr Val Leu       Ile Ile                                                                              200             - #    205             - #    210             - #        215                                                                           - -      Met Gly Thr Tyr Val Ser Ser Val - # Pro Arg                                           - #   220              - #   225                             - -  - - (2) INFORMATION FOR SEQ ID NO:113:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 256 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                             - -      Met Pro Arg Ser Arg Ala Leu Ile - # Leu Gly Val Leu Ala Leu        Thr Thr                                                                              -25             - #-20                 - #    -15             - #        -10                                                                           - -      Met Leu Ser Leu Cys Gly Gly Glu - # Asp Asp Ile Glu Ala Asp        His Val                                                                                          -5 - #                  - #   1               - #5           - -      Gly Ser Tyr Gly Ile Thr Phe Tyr - # Gln Ser Pro Gly Asp Ile        Gly Gln                                                                                      10     - #             15     - #             20                  - -      Tyr Thr Phe Glu Phe Asp Gly Asp - # Glu Leu Phe Tyr Val Asp       Leu Asp                                                                                  25         - #         30         - #         35                      - -      Lys Lys Glu Thr Val Trp Met Leu - # Pro Glu Phe Ala Gln Leu       Arg Arg                                                                              40             - #     45             - #     50             - #         55                                                                            - -      Phe Glu Pro Gln Gly Gly Leu Gln - # Asn Ile Ala Thr Gly Lys        His Asn                                                                                           - #   60               - #   65               - #         70                                                                               - -      Leu Glu Ile Leu Thr Lys Arg Ser - # Asn Ser Thr Pro Ala Thr       Asn Glu                                                                                          75 - #                 80 - #                 85             - -      Ala Pro Gln Ala Thr Val Phe Pro - # Lys Ser Pro Val Leu Leu        Gly Gln                                                                                      90     - #             95     - #             100                 - -      Pro Asn Thr Leu Ile Cys Phe Val - # Asp Asn Ile Phe Pro Pro       Val Ile                                                                                  105         - #        110         - #        115                     - -      Asn Ile Thr Trp Leu Arg Asn Ser - # Lys Ser Val Thr Asp Gly       Val Tyr                                                                              120             - #    125             - #    130             - #        135                                                                           - -      Glu Thr Ser Phe Phe Val Asn Arg - # Asp Tyr Ser Phe His Lys        Leu Ser                                                                                           - #   140              - #   145              - #         150                                                                              - -      Tyr Leu Thr Phe Ile Pro Ser Asp - # Asp Asp Ile Tyr Asp Cys       Lys Val                                                                                          155 - #                160 - #                165            - -      Glu His Trp Gly Leu Glu Glu Pro - # Val Leu Lys His Trp Glu        Pro Glu                                                                                      170     - #            175     - #            180                 - -      Ile Pro Ala Pro Met Ser Glu Leu - # Thr Glu Thr Val Val Cys       Ala Leu                                                                                  185         - #        190         - #        195                     - -      Gly Leu Ser Val Gly Leu Val Gly - # Ile Val Val Gly Thr Ile       Phe Ile                                                                              200             - #    205             - #    210             - #        215                                                                           - -      Ile Gln Gly Leu Arg Ser Gly Gly - # Thr Ser Arg His Pro Gly        Pro Leu                                                                                           - #   220              - #   225              - #         230                                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:114:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 256 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 7                                                               (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                             - -      Met Ala Thr Ile Gly Ala Leu Val - # Leu Arg Phe Phe Phe Ile        Ala Val                                                                              -25             - #-20                 - #-15                 -        #-10                                                                             - -      Leu Met Ser Ser Gln Lys Ser Trp - # Ala Ile Lys Glu Glu His       Thr Xaa                                                                                          -5 - #                 1 - #                  - #5           - -      Ile Ile Gln Ala Glu Phe Tyr Leu - # Leu Pro Asp Lys Arg Gly        Glu Phe                                                                                      10     - #             15     - #             20                  - -      Met Phe Asp Phe Asp Gly Asp Glu - # Ile Phe His Val Asp Ile       Glu Lys                                                                                  25         - #         30         - #         35                      - -      Ser Glu Thr Ile Trp Arg Leu Glu - # Glu Phe Ala Lys Phe Ala       Ser Phe                                                                              40             - #     45             - #     50             - #         55                                                                            - -      Glu Ala Gln Gly Ala Leu Ala Asn - # Ile Ala Val Asp Lys Ala        Asn Leu                                                                                           - #   60               - #   65               - #         70                                                                               - -      Asp Val Met Lys Glu Arg Ser Asn - # Asn Thr Pro Ser Ala Asn       Val Ala                                                                                          75 - #                 80 - #                 85             - -      Pro Glu Val Thr Val Leu Ser Arg - # Ser Pro Val Asn Leu Gly        Glu Pro                                                                                      90     - #             95     - #             100                 - -      Asn Ile Leu Ile Cys Phe Ile Asp - # Lys Phe Ser Pro Pro Val       Val Asn                                                                                  105         - #        110         - #        115                     - -      Val Thr Trp Leu Arg Asn Gly Arg - # Pro Val Thr Glu Gly Val       Ser Glu                                                                              120             - #    125             - #    130             - #        135                                                                           - -      Thr Val Phe Leu Pro Arg Asp Asp - # His Leu Phe Arg Lys Phe        His Tyr                                                                                           - #   140              - #   145              - #         150                                                                              - -      Leu Thr Phe Leu Pro Ser Thr Asp - # Asp Phe Tyr Asp Cys Glu       Val Asp                                                                                          155 - #                160 - #                165            - -      His Trp Gly Leu Glu Glu Pro Leu - # Arg Lys Ala Trp Glu Phe        Glu Glu                                                                                      170     - #            175     - #            180                 - -      Lys Thr Leu Leu Pro Glu Thr Lys - # Glu Asn Val Val Cys Ala       Leu Gly                                                                                  185         - #        190         - #        195                     - -      Leu Phe Val Gly Leu Val Gly Ile - # Val Val Gly Ile Ile Leu       Ile Met                                                                              200             - #    205             - #    210             - #        215                                                                           - -      Lys Gly Ile Lys Lys Arg Asn Val - # Val Glu Arg Arg Gln Gly        Ala Leu                                                                                           - #   220              - #   225              - #         230                                                                              - -  - - (2) INFORMATION FOR SEQ ID NO:115:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 266 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                             - -      Met Val Cys Leu Lys Leu Pro Gly - # Gly Ser Cys Met Thr Ala       Leu Thr                                                                              -29             - #-25                 - #-20                 -        #-15                                                                             - -      Val Thr Leu Met Val Leu Ser Ser - # Pro Leu Ala Leu Ala Gly       Asp Thr                                                                                          -10 - #                -5  - #                1              - -      Arg Pro Arg Phe Leu Trp Gln Leu - # Lys Phe Glu Cys His Phe        Phe Asn                                                                                      5     - #              10    - #              15                  - -      Gly Thr Glu Arg Val Arg Leu Leu - # Glu Arg Cys Ile Tyr Asn       Gln Glu                                                                                  20         - #         25         - #         30                      - -      Glu Ser Val Arg Phe Asp Ser Asp - # Val Gly Glu Tyr Arg Ala       Val Thr                                                                              35             - #     40             - #     45             - #         50                                                                            - -      Glu Leu Gly Arg Pro Asp Ala Glu - # Tyr Trp Asn Ser Gln Lys        Asp Leu                                                                                           - #   55               - #   60               - #         65                                                                               - -      Leu Glu Gln Arg Arg Ala Ala Val - # Asp Thr Tyr Cys Arg His       Asn Tyr                                                                                          70 - #                 75 - #                 80             - -      Gly Val Gly Glu Ser Phe Thr Val - # Gln Arg Arg Val Glu Pro        Lys Val                                                                                      85     - #             90     - #             95                  - -      Thr Val Tyr Pro Ser Lys Thr Gln - # Pro Leu Gln His His Asn       Leu Leu                                                                                  100         - #        105         - #        110                     - -      Val Cys Ser Val Ser Gly Phe Tyr - # Pro Gly Ser Ile Glu Val       Arg Trp                                                                              115             - #    120             - #    125             - #        130                                                                           - -      Phe Arg Asn Gly Gln Glu Glu Lys - # Ala Gly Val Val Ser Thr        Gly Leu                                                                                           - #   135              - #   140              - #         145                                                                              - -      Ile Gln Asn Gly Asp Trp Thr Phe - # Gln Thr Leu Val Met Leu       Glu Thr                                                                                          150 - #                155 - #                160            - -      Val Pro Arg Ser Gly Glu Val Tyr - # Thr Cys Gln Val Glu His        Pro Ser                                                                                      165     - #            170     - #            175                 - -      Val Thr Ser Pro Leu Thr Val Glu - # Trp Arg Ala Arg Ser Glu       Ser Ala                                                                                  180         - #        185         - #        190                     - -      Gln Ser Lys Met Leu Ser Gly Val - # Gly Gly Phe Val Leu Gly       Leu Leu                                                                              195             - #    200             - #    205             - #        210                                                                           - -      Phe Leu Gly Ala Gly Leu Phe Ile - # Tyr Phe Arg Asn Gln Lys        Gly His                                                                                           - #   215              - #   220              - #         225                                                                              - -      Ser Gly Leu Gln Pro Thr Gly Phe - # Leu Ser                                          230 - #                235                                    - -  - - (2) INFORMATION FOR SEQ ID NO:116:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 269 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 226..233                                                        (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                          amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                             - -      Met Ser Trp Lys Lys Ser Leu Arg - # Ile Pro Gly Asp Leu Arg        Val Ala                                                                                      -30     - #            -25     - #            -20                 - -      Thr Val Thr Leu Met Leu Ala Ile - # Leu Ser Ser Ser Leu Ala       Glu Gly                                                                                  -15         - #        -10         - #        -5                      - -      Arg Asp Ser Pro Glu Asp Phe Val - # Tyr Gln Phe Lys Gly Leu       Cys Tyr                                                                              1             - #  5                - #   10               - #         15                                                                               - -      Phe Thr Asn Gly Thr Glu Arg Val - # Arg Gly Val Thr Arg His       Ile Tyr                                                                                          20 - #                 25 - #                 30             - -      Asn Arg Glu Glu Tyr Val Arg Phe - # Asp Ser Asp Val Gly Val        Tyr Arg                                                                                      35     - #             40     - #             45                  - -      Ala Val Thr Pro Gln Gly Arg Pro - # Val Ala Glu Tyr Trp Asn       Ser Gln                                                                                  50         - #         55         - #         60                      - -      Lys Glu Val Leu Glu Gly Ala Arg - # Ala Ser Val Asp Arg Val       Cys Arg                                                                              65             - #     70             - #     75             - #         80                                                                            - -      His Asn Tyr Glu Val Ala Tyr Arg - # Gly Ile Leu Gln Arg Arg        Val Glu                                                                                           - #   85               - #   90               - #         95                                                                               - -      Pro Thr Val Thr Ile Ser Pro Ser - # Arg Thr Glu Ala Leu Asn       His His                                                                                          100 - #                105 - #                110            - -      Asn Leu Leu Ile Cys Ser Val Thr - # Asp Phe Tyr Pro Ser Gln        Ile Lys                                                                                      115     - #            120     - #            125                 - -      Val Arg Trp Phe Arg Asn Asp Gln - # Glu Glu Thr Ala Gly Val       Val Ser                                                                                  130         - #        135         - #        140                     - -      Thr Pro Leu Ile Arg Asn Gly Asp - # Trp Thr Phe Gln Ile Leu       Val Met                                                                              145             - #    150             - #    155             - #        160                                                                           - -      Leu Glu Met Thr Pro Gln Arg Gly - # Asp Val Tyr Thr Cys His        Val Glu                                                                                           - #   165              - #   170              - #         175                                                                              - -      His Pro Ser Leu Gln Ser Pro Ile - # Thr Val Glu Trp Arg Ala       Gln Ser                                                                                          180 - #                185 - #                190            - -      Glu Ser Ala Gln Ser Lys Met Leu - # Ser Gly Val Gly Gly Phe        Val Leu                                                                                      195     - #            200     - #            205                 - -      Gly Leu Ile Phe Leu Gly Leu Gly - # Leu Ile Ile Arg Gln Arg       Ser Arg                                                                                  210         - #        215         - #        220                     - -      Lys Xaa Xaa Xaa Xaa Xaa Xaa Xaa - # Xaa Gly Leu Leu His                 225             - #    230             - #    235                         - -  - - (2) INFORMATION FOR SEQ ID NO:117:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 259 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (ix) FEATURE:                                                                  (A) NAME/KEY: Region                                                          (B) LOCATION: 24..25                                                          (D) OTHER INFORMATION: - #/note= "Xaa is an unidentified                           amino aci - #d residue."                                        - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                             - -      Met Val Leu Gln Val Ser Ala Ala - # Pro Arg Thr Val Ala Leu        Thr Ala                                                                              -28         -25   - #              -20   - #              -15            - -      Leu Leu Met Val Leu Leu Thr Ser - # Val Val Gln Gly Arg Ala        Thr Pro                                                                                      -10     - #            -5      - #            1                   - -      Glu Asn Tyr Leu Phe Gln Gly Arg - # Gln Glu Cys Tyr Ala Phe       Asn Gly                                                                              5             - #      10            - #      15            - #          20                                                                            - -      Thr Gln Arg Xaa Xaa Phe Leu Glu - # Arg Tyr Ile Tyr Asn Arg        Glu Glu                                                                                           - #   25               - #   30               - #         35                                                                               - -      Phe Val Arg Phe Asp Ser Asp Val - # Gly Glu Phe Arg Ala Val       Thr Glu                                                                                          40 - #                 45 - #                 50             - -      Leu Gly Arg Pro Asp Glu Glu Tyr - # Trp Asn Ser Gln Lys Asp        Ile Leu                                                                                      55     - #             60     - #             65                  - -      Glu Glu Glu Arg Ala Val Pro Asp - # Arg Met Cys Arg His Asn       Tyr Glu                                                                                  70         - #         75         - #         80                      - -      Leu Gly Gly Pro Met Thr Leu Gln - # Arg Arg Val Gln Pro Arg       Val Asn                                                                              85             - #     90             - #     95             - #         100                                                                           - -      Val Ser Pro Ser Lys Lys Gly Pro - # Leu Gln His His Asn Leu        Leu Val                                                                                           - #   105              - #   110              - #         115                                                                              - -      Cys His Val Thr Asp Phe Tyr Pro - # Gly Ser Ile Gln Val Arg       Trp Phe                                                                                          120 - #                125 - #                130            - -      Leu Asn Gly Gln Glu Glu Thr Ala - # Gly Val Val Ser Thr Asn        Leu Ile                                                                                      135     - #            140     - #            145                 - -      Arg Asn Gly Asp Trp Thr Phe Gln - # Ile Leu Val Met Leu Glu       Met Thr                                                                                  150         - #        155         - #        160                     - -      Pro Gln Gln Gly Asp Val Tyr Thr - # Cys Gln Val Glu His Thr       Ser Leu                                                                              165             - #    170             - #    175             - #        180                                                                           - -      Asp Ser Pro Val Thr Val Glu Trp - # Lys Ala Gln Ser Asp Ser        Ala Arg                                                                                           - #   185              - #   190              - #         195                                                                              - -      Ser Lys Thr Leu Thr Gly Ala Gly - # Gly Phe Val Leu Gly Leu       Ile Ile                                                                                          200 - #                205 - #                210            - -      Cys Gly Val Gly Ile Phe Met His - # Arg Arg Ser Lys Lys Val        Gln Arg                                                                                      215     - #            220     - #        225                     - -      Gly Ser Ala                                                                  230                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:118:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 273 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                             - -      Met Gly Ser Gly Trp Val Pro Trp - # Val Val Ala Leu Leu Val       Asn Leu                                                                                  -25         - #        -20         - #        -15                     - -      Thr Arg Leu Asp Ser Ser Met Thr - # Gln Gly Thr Asp Ser Pro       Glu Asp                                                                              -10             - #    -5              - #    1              - # 5       - -      Phe Val Ile Gln Ala Lys Ala Asp - # Cys Tyr Phe Thr Asn Gly        Thr Glu                                                                                          10 - #                 15 - #                 20             - -      Lys Val Gln Phe Val Val Arg Phe - # Ile Phe Asn Leu Glu Glu        Tyr Val                                                                                      25     - #             30     - #             35                  - -      Arg Phe Asp Ser Asp Val Gly Met - # Phe Val Ala Leu Thr Lys       Leu Gly                                                                                  40         - #         45         - #         50                      - -      Gln Pro Asp Ala Glu Gln Trp Asn - # Ser Arg Leu Asp Leu Leu       Glu Arg                                                                              55             - #     60             - #     65             - #         70                                                                            - -      Ser Arg Gln Ala Val Asp Gly Val - # Cys Arg His Asn Tyr Arg        Leu Gly                                                                                           - #   75               - #   80               - #         85                                                                               - -      Ala Pro Phe Thr Val Gly Arg Lys - # Val Gln Pro Glu Val Thr       Val Tyr                                                                                           - #90                 9 - #5                  - #100        - -      Pro Glu Arg Thr Pro Leu Leu His - # Gln His Asn Leu Leu His        Cys Ser                                                                                      105     - #            110     - #            115                 - -      Val Thr Gly Phe Tyr Pro Gly Asp - # Ile Lys Ile Lys Trp Phe       Leu Asn                                                                                  120         - #        125         - #        130                     - -      Gly Gln Glu Glu Arg Ala Gly Val - # Met Ser Thr Gly Pro Ile       Arg Asn                                                                              135             - #    140             - #    145             - #        150                                                                           - -      Gly Asp Trp Thr Phe Gln Thr Val - # Val Met Leu Glu Met Thr        Pro Glu                                                                                           - #   155              - #   160              - #         165                                                                              - -      Leu Gly His Val Tyr Thr Cys Leu - # Val Asp His Ser Ser Leu       Leu Ser                                                                                          170 - #                175 - #                180            - -      Pro Val Ser Val Glu Trp Arg Ala - # Gln Ser Glu Tyr Ser Trp        Arg Lys                                                                                      185     - #            190     - #            195                 - -      Met Leu Ser Gly Ile Ala Ala Phe - # Leu Leu Gly Leu Ile Phe       Leu Leu                                                                                  200         - #        205         - #        210                     - -      Val Gly Ile Val Ile Gln Leu Arg - # Ala Gln Lys Gly Tyr Val       Arg Thr                                                                              215             - #    220             - #    225             - #        230                                                                           - -      Gln Met Ser Gly Asn Glu Val Ser - # Arg Ala Val Leu Leu Pro        Gln Ser                                                                                           - #   235              - #   240              - #         245                                                                              - -      Gln                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:119:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 265 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                             - -      Met Ala Leu Gln Ile Pro Ser Leu - # Leu Leu Ser Ala Ala Val       Val Val                                                                                      -25     - #            -20     - #            -15                 - -      Leu Met Val Leu Ser Ser Pro Arg - # Thr Glu Gly Gly Asn Ser       Glu Arg                                                                                  -10         - #        -5          - #        1          - #         5                                                                             - -      His Phe Val Ala Gln Leu Lys Gly - # Glu Cys Tyr Phe Thr Asn        Gly Thr                                                                                           - #   10               - #   15               - #         20                                                                               - -      Gln Arg Ile Arg Ser Val Asn Arg - # Tyr Ile Tyr Asn Arg Glu       Glu Trp                                                                                          25 - #                 30 - #                 35             - -      Val Arg Phe Asp Ser Asp Val Gly - # Glu Tyr Arg Ala Val Thr        Glu Leu                                                                                      40     - #             45     - #             50                  - -      Gly Arg Pro Asp Ala Glu Tyr Trp - # Asn Ser Gln Pro Glu Ile       Leu Glu                                                                                  55         - #         60         - #         65                      - -      Arg Thr Arg Ala Glu Val Asp Thr - # Val Cys Arg His Asn Tyr       Glu Gly                                                                              70             - #     75             - #     80             - #         85                                                                            - -      Val Glu Thr His Thr Ser Leu Arg - # Arg Leu Glu Gln Pro Asn        Val Ala                                                                                           - #   90               - #   95               - #         100                                                                              - -      Ile Ser Leu Ser Arg Thr Glu Ala - # Leu Asn His His Asn Thr       Leu Val                                                                                          105 - #                110 - #                115            - -      Cys Ser Val Thr Asp Phe Tyr Pro - # Ala Lys Ile Lys Val Arg        Trp Phe                                                                                      120     - #            125     - #            130                 - -      Arg Asn Gly Gln Glu Glu Thr Val - # Gly Val Ser Ser Thr Gln       Leu Ile                                                                                  135         - #        140         - #        145                     - -      Arg Asn Gly Asp Trp Thr Phe Gln - # Val Leu Val Met Leu Glu       Met Thr                                                                              150             - #    155             - #    160             - #        165                                                                           - -      Pro His Gln Gly Glu Val Tyr Thr - # Cys His Val Glu His Pro        Ser Leu                                                                                           - #   170              - #   175              - #         180                                                                              - -      Lys Ser Pro Ile Thr Val Glu Trp - # Arg Ala Gln Ser Glu Ser       Ala Arg                                                                                          185 - #                190 - #                195            - -      Ser Lys Met Leu Ser Gly Ile Gly - # Gly Cys Val Leu Gly Val        Ile Phe                                                                                      200     - #            205     - #            210                 - -      Leu Gly Leu Gly Leu Phe Ile Arg - # His Arg Ser Gln Lys Gly       Pro Arg                                                                                  215         - #        220         - #        225                     - -      Gly Pro Pro Pro Ala Gly Leu Leu - # Gln                                  230             - #    235                                                - -  - - (2) INFORMATION FOR SEQ ID NO:120:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 264 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                             - -      Met Val Trp Leu Pro Arg Val Pro - # Cys Val Ala Ala Val Ile       Leu Leu                                                                                      -25     - #            -20     - #            -15                 - -      Leu Thr Val Leu Ser Pro Pro Val - # Ala Leu Val Arg Asp Thr       Pro Pro                                                                                  -10         - #        -5          - #        1          - #         5                                                                             - -      Arg Phe Leu Glu Tyr Val Thr Ser - # Glu Cys His Phe Tyr Asn        Gly Thr                                                                                           - #   10               - #   15               - #         20                                                                               - -      Gln His Val Arg Phe Leu Glu Arg - # Phe Ile Tyr Asn Arg Glu       Glu Asn                                                                                          25 - #                 30 - #                 35             - -      Leu Arg Phe Asp Ser Asp Val Gly - # Glu Tyr Arg Ala Val Thr        Glu Leu                                                                                      40     - #             45     - #             50                  - -      Gly Arg Pro Asp Ala Glu Asn Trp - # Asn Ser Gln Pro Glu Ile       Leu Glu                                                                                  55         - #         60         - #         65                      - -      Asp Ala Arg Ala Ser Val Asp Thr - # Tyr Cys Arg His Asn Tyr       Glu Ile                                                                              70             - #     75             - #     80             - #         85                                                                            - -      Ser Asp Lys Phe Leu Val Arg Arg - # Arg Val Glu Pro Thr Val        Thr Val                                                                                           - #   90               - #   95               - #         100                                                                              - -      Tyr Pro Thr Lys Thr Gln Pro Leu - # Glu His His Asn Leu Leu       Val Cys                                                                                          105 - #                110 - #                115            - -      Ser Val Ser Asp Phe Tyr Pro Gly - # Asn Ile Glu Val Arg Trp        Phe Arg                                                                                      120     - #            125     - #            130                 - -      Asn Gly Lys Glu Glu Glu Thr Gly - # Ile Val Ser Thr Gly Leu       Val Arg                                                                                  135         - #        140         - #        145                     - -      Asn Gly Asp Trp Thr Phe Gln Thr - # Leu Val Met Leu Glu Trp       Val Pro                                                                              150             - #    155             - #    160             - #        165                                                                           - -      Gln Ser Gly Glu Val Tyr Thr Cys - # Gln Val Glu His Pro Ser        Leu Thr                                                                                           - #   170              - #   175              - #         180                                                                              - -      Asp Pro Val Thr Val Glu Trp Lys - # Ala Gln Ser Thr Ser Ala       Gln Asn                                                                                          185 - #                190 - #                195            - -      Lys Met Leu Ser Gly Val Gly Gly - # Phe Val Leu Gly Leu Leu        Phe Leu                                                                                      200     - #            205     - #            210                 - -      Gly Ala Gly Leu Phe Ile Tyr Phe - # Arg Asn Gln Lys Gly Gln       Ser Glu                                                                                  215         - #        220         - #        225                     - -      Leu Gln Pro Thr Gly Leu Leu Ser                                          230             - #    235                                                - -  - - (2) INFORMATION FOR SEQ ID NO:121:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                             - -      Glu Phe Ser Lys Phe Gly                                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:122:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                             - -      Val Leu Arg Gln Arg                                                      1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:123:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                             - -      Leu Phe Arg Arg Arg Arg                                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:124:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                             - -      Glu Val Ala Tyr                                                          1                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:125:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                             - -      Glu Val Ala Phe                                                          1                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:126:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                             - -      Glu Val Ala Gly                                                          1                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:127:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino - #acids                                                  (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                             - -      Gln Leu Glu Leu                                                          1                                                                         - -  - - (2) INFORMATION FOR SEQ ID NO:128:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                             - -      Thr Tyr Gln Arg Thr Arg Ala Leu - # Val                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:129:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                             - -      Ser Tyr Phe Pro Glu Ile Thr His - # Ile                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:130:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                             - -      Ile Tyr Ala Thr Val Ala Gly Ser - # Leu                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:131:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                             - -      Val Tyr Gln Ile Leu Ala Ile Tyr - # Ala                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:132:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                             - -      Asn Val Gly Thr Tyr Val                                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:133:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                             - -      Glu Asn Gly Lys Glu Thr                                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:134:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                             - -      Arg Tyr Leu Lys Asn Gly Lys Glu - # Thr                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:135:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                             - -      Lys Tyr Gln Ala Val Thr Thr Thr - # Leu                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:136:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                             - -      Ser Tyr Ile Pro Ser Ala Glu Lys - # Ile                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:137:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                             - -      Ser Tyr Val Pro Ser Ala Glu Gln - # Ile                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:138:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                             - -      Ala Ser Asn Glu Asn Met Glu Thr - # Met                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:139:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                             - -      Ser Gly Pro Ser Asn Thr Pro Pro - # Glu Ile                              1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:140:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                             - -      Ser Gly Val Glu Asn Pro Gly Gly - # Tyr Cys Leu                          1             - #  5                - #   10                              - -  - - (2) INFORMATION FOR SEQ ID NO:141:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                             - -      Ser Ala Ile Asn Asn Tyr                                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:142:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                             - -      Arg Gly Tyr Val Tyr Gln Gly Leu                                          1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:143:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                             - -      Ser Ile Ile Asn Phe Glu Lys Leu                                          1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:144:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                             - -      Ala Pro Gly Asn Tyr Pro Ala Leu                                          1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:145:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                             - -      Ile Leu Lys Glu Pro Val His Gly - # Val                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:146:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                             - -      Phe Leu Gln Ser Arg Pro Glu Pro - # Thr                                  1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:147:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                             - -      Ala Met Gln Met Leu Lys Glu                                              1             - #  5                                                      - -  - - (2) INFORMATION FOR SEQ ID NO:148:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino - #acids                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                             - -      Gln Met Lys Asp Cys Thr Glu Arg - # Gln                                  1             - #  5                                                   __________________________________________________________________________

What is claimed is:
 1. A recombinant DNA molecule comprising a DNAsequence encoding an altered MHC Class I determinant;wherein saidaltered MHC Class I determinant comprises a polypeptide comprising α₁,α₂, α₃, and β₂ -microglobulin domains; wherein the α₃ domain has acarboxyl terminus, and the β₂ -microglobulin domain has an aminoterminus covalently linked to said carboxyl terminus by a spacer;wherein said polypeptide contains a binding site for an antigen that maybe associated with the polypeptide, and when associated, the polypeptideand the antigen together are recognizable by a mammalian T cellreceptor; and wherein said spacer is a nucleotide sequence encoding apolypeptide.
 2. A recombinant DNA molecule of claim 1, wherein saidspacer encodes 2-30 amino acids.
 3. A recombinant DNA molecule of claim1 or 2, wherein said molecule contains an expression control sequenceoperably linked to said DNA sequence.
 4. A host transformed with therecombinant DNA molecule of claim 3.